CZ20033475A3 - Pyrrolidine oxadiazole- and thiadiazole oxime derivatives being oxytocin receptor antagonists. - Google Patents

Abstract

The present invention is related to pyrrolidine oxadiazole and thiadiazole derivatives for use as pharmaceutically active compounds, as well as pharmaceutical formulations containing such pyrrolidine oxadiazole derivatives. Said pyrrolidine derivatives are useful in the treatment and/or prevention of preterm labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including preterm labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation. (I) B is a oxadiazole or thiadiazole group.

Description

Technical field

The present invention relates to novel pyrrolidinoxadiazole and pyrrolidinothiadiazole derivatives, particularly for use as medicaments, as well as pharmaceutical compositions containing these pyrrolidine derivatives. Said derivatives are suitable for the treatment and / or prevention of preterm labor, preterm labor and painful menstruation. Preferably, the pyrrolidine derivatives have a modulating, especially antagonistic, effect of the oxytocin receptor. More preferably, the compounds may be used in the treatment and / or prevention of oxytocin-related diseases including premature labor, premature labor and painful menstruation.

BACKGROUND OF THE INVENTION

In the field of obstetrics, one of the most important problems is the regulation of premature labor and premature labor, as they are the main cause of perinatal disease and mortality.

The use of magnesium sulfate and ethanol was recommended for the treatment of premature labor. However, magnesium sulphate at plasma concentrations above the therapeutic range of 4 to 8 mg / dl can inhibit the transmission of nerve impulses through the heart and neuromuscular transmission, respiratory problems and cardiac arrest, therefore, this composition is unsuitable, especially when renal function is impaired.

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- 2 Ethanol is effective in preventing premature labor but does not adequately reduce the incidence of fetal respiratory problems. Thus, ethanol is considered to have a negative effect on the fetus.

Two other therapeutic agents fall into the following groups:

(a) β 2 -adrenergic agonists; or

b) oxytocin antagonists.

The 32-adrenergic receptor generally exerts an inhibitory effect in the cells where it is expressed (muscles, heart, uterus, etc.). 32-adrenergic agonists are used to activate said receptor inhibitory effect. Therefore, β 2 -adrenergic agonists are sympathomimetics that, inter alia, inhibit uterine contractions. Known β2adrenergic agonists for the treatment of preterm labor are Ritodrin, Terbutalin and Albuterol.

Ritodrine (for example (R *, S *) - hydroxy-alpha - [1 - [[2- (4-hydroxyphenyl) ethyl] amino] ethyl] benzenemethanol; see US 3,410,944 NVPhilips) is a major β2adrenergic agonist but causes many cardiovascular and metabolic side effects in a pregnant woman, including tachycardia, increased renin secretion, hyperglycemia (reactive hypoglycaemia in the infant).

Terbutaline (e.g., 5- [2 - [(1,1-dimethylethyl) amino] -1-hydroxyethyl] -1,3-benzenediol, US 3,937,838, Draco) and Albuterol (a ¹ - [[(1,1-dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol (US 3,644,353, Allen and Hanburys) are other βΣββββββ β agonists and have similar side effects to Ritodrine.

A more current approach to treating premature labor is the use of oxytocin antagonists.

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Oxytocin (OT) is a peptide hormone and causes the uterine contraction of mammals during labor. The corresponding oxytocin receptor is similar to the vasopressin receptors V _1a and V ₂ and acts via a G protein-coupled receptor associated with phospholipase C activation and increases in IP ₃ , which releases Ca ²⁺ from intracellular stores. Increasing intracellular calcium, which in turn causes increased smooth muscle contraction by activation of the myosin kinase weak chain. The oxytocin (OT) receptors increase significantly during pregnancy. The concentration of OT receptors has been shown to correlate with spontaneous uterine activity (M. Maggi et al. J.Cin.Endocrmol Metabol., 70; 1142, 1990). In the last few years, research has shown that the hormone oxytocin may be a physiological initiator of labor in many mammalian species, including humans. It is further believed that oxytocin produces this effect in two parts:

by direct contraction of the uterine muscle and by increasing the synthesis and release of contractile prostaglandins from the uterine mucosa / decidua. In addition, these prostaglandins may be important in the process of releasing suppository division during labor.

By these mechanisms, the process of labor (early and premature) is initiated by an increased uterine sensitivity to oxytocin, resulting in part from an increase in the amount of oxytocin receptors in this tissue.

By blocking oxytocin, the direct (contractile) and indirect (increased prostaglandin synthesis) effect of oxytocin on the uterus can be achieved. The oxytocin blocker or antagonist is believed to be more effective in treating preterm labor than conventional methods.

Atosiban (e.g. oxytocin, 1- (3-mercaptopropionic acid) -2- (O-ethyl-D-tyrosine) -4-L-threonine-8-L-ornithine) is a cyclic pentapeptide that is

The 4 best known OT antagonists (WO 9501368, Ferring AB; J. Reprod. Fertin., 101 (2), 345-52 (English) 1994); Am. J. Obstet. Gynecol., 170 (2), 474-8 1994). The principal disadvantage of using peptide antagonists such as atosiban is the problem of low oral bioavailability, consisting of intestinal degradation (degradation in the intestines). Therefore, it must be administered parenterally (extracorporeally).

Also WO 96/22775 and US-5,756,497 (Merck) disclose benzoxazinyl piperidines or benzoxazinones as OT receptor antagonists. Indanylpiperidines and tolylpiperazines are listed by Evans et al., In J-Med-Chem., 35, 3919 (1992) as orally deliverable OT antagonists.

The compounds of the present invention have been found to be oxytocin antagonists and bind to the oxytocin receptor. When the oxytocin receptor binds with the compounds of the present invention, oxytocin is antagonized by being blocked from its receptor and is therefore unable to exert its biological or pharmacological effects. The compounds of the present invention are therefore suitable for the treatment and prevention of preterm labor and preterm labor. The compounds are also suitable for arresting labor in preparation for caesarean delivery. In particular, the compounds of the present invention are suitable for the treatment and prevention of oxytocin-related disorders of animals, preferably mammals and especially humans. Another object of the present invention is to provide a method of antagonizing oxytocin functions in mammalian diseases. It is also an object of the present invention to provide a method for the prevention or treatment of oxytoxin-related premature labor diseases by antagonizing the binding of oxytocin to its receptor.

The compounds of the present invention are also useful in the treatment of painful menstruation, which may be defined as cyclic pain associated with menstruation during ovulation cycles. It is believed that pain arises from

uterine contractions and ischemia, possibly due to the action of prostaglandins, produced by the secretion of the uterine mucosa. By blocking the direct or indirect effect of oxytocin on the uterus, an oxytocin antagonist is more effective for the treatment of painful menstruation than conventional methods.

SUMMARY OF THE INVENTION

The following provides definitions of the various chemical moieties that make up the compounds of the invention and can be used uniformly throughout the specification and claims, without otherwise defining a broader definition.

_"Ci-Ce alkyl" means monovalantní alkyl groups having 1 to 6 carbon atoms. For example, the term may be represented by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.

"Aryl" means an unsaturated aromatic carboxyl group of 6 to 14 carbon atoms having one ring (for example phenyl) or multiple condensed rings (for example naphthyl). Aryl preferably includes phenyl, naphthyl, phenanthrenyl and the like.

"C 1 -C ₆ -alkyl aryl" means C 1 -C ₆ -alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.

"Heteroaryl" means a monocyclic heteroaromatic group or a fused-bicyclic or tricyclic heteroaromatic group. Specific examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3oxadiazolyl, 1 , 2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-6 triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydrojbenzofuryl, isobenzofuryl , benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1,2-a] pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, naphthyridinyl, naphthyridine , pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl , pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

"C 1 -C ₆ -alkyl heteroaryl" means C 1 -C ₆ -alkyl groups having a heteroaryl substituent, including 2-furalmethyl, 2-thienylmethyl, 2- (1H-indol-3-yl-ethyl) and the like.

"C 2 -C ₆ -alkenyl" means alkenyl groups having 2 to 6 carbon atoms and having at least 1 or 2 alkenyl unsaturation sites. The alkenyl groups preferably include ethenyl (-CH = CH ₂ ), n-2-propenyl (allyl, -CH ₂ CH = CH 2) and the like.

"C ₂ -C ₆ -alkenyl aryl" means a C ₂ -C ₆ -alkenyl group having an aryl substituent, including 2-phenylvinyl and the like.

"C ₂ -C ₆ -alkenyl heteroaryl" means C ₂ -C ₆ -alkyl groups having a heteroaryl substituent, including 2- (3-pyridinyl) vinyl and the like.

"C 2 -C 6 -alkynyl" means alkynyl groups preferably having 2 to 6 carbon atoms and having at least 1 to 2 alkynyl unsaturation sites, preferred alkynyl groups include ethynyl (-C =CH), propargyl (-CH ₂ C =CH) ) etc.

"C ₂ -C ₆ -alkynyl aryl" means C ₂ -C ₆ -alkynyl groups having an aryl substituent, including phenylethynyl and the like.

- 7 "C ₂ -C ₆ -alkynyl heteroaryl" refers to C ₂ -C _s -alkynyl groups having a heteroaryl substituent, including 2-thienylethinyl and the like.

"C 3 -C 8 -cycloalkyl" means a saturated carbocyclic group of 3 to 8 carbon atoms having one ring (for example cyclohexyl) or multiple condensed rings (for example norbornyl). Preferred cycloalkyl includes cyclopentyl, cyclohexal, norbornyl and the like.

"C 1 -C ₆ -alkyl cycloalkyl" means C 1 -C ₆ -alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl and the like.

"Heterocycloalkyl" means a C ₃ -C ₈ -cycloalkyl group as defined above wherein up to 3 carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, NR, wherein R is defined as hydrogen or methyl. Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine and the like.

"C 1 -C ₆ -alkyl heterocycloalkyl" means CC ₅ -alkyl groups having a heterocycloalkyl substituent, including 2- (1-pyrrolidinyl) ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl) methyl and the like.

"Carboxy" means -C (O) OH.

"C 1 -C ₆ -alkyl carboxy" means C 1 -C ₆ -alkyl groups having a carboxy substituent, including 2-carboxyethyl and the like.

- 8 "Acyl" means -C (O) R, wherein R comprises H, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ - C ₈ -cycloalkyl ", heterocycloalkyl" heterocycloalkyl ¹ ', "aryl", "heteroaryl", "C 1 -C ₆ -alkyl aryl" or "C 1 -C ₆ -alkyl heteroaryl", "C ₂ -C ₆ -alkenyl aryl""C ₂ -C _s alkenyl heteroaryl", "C ₂ -C _s -alkynyl aryl", "C ₂ -C ₆ -alkynyl heteroaryl", _"Ci-C6-alkyl cycloalkyl", _"Ci-C6-alkyl heterocycloalkyl ".

"C 1 -C ₆ -alkyl acyl" means C 1 -C ₆ -alkyl groups having an acyl substituent, including 2-acetylethyl and the like.

"Aryl acyl" means aryl groups having an acyl substituent, including 2-acetylphenyl and the like.

"Heteroaryl acyl" means heteroaryl groups having an acyl substituent, including 2-acetylpyridyl and the like.

"C ₃ -C ₈ - (hetero) cycloalkyl acyl" means a 3- to 8-membered cycloalkyl or heterocycloalkyl group having an acyl substituent.

"Acyloxy" means a group -OC (O) R wherein R includes "C 1 -C ₆ -alkyl", "C ₂ -C ₆ alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ -C ₈ -cycloalkyl"",Heterocycloalkyl" heterocycloalkyl "," aryl "," heteroaryl "," C 1 -C ₆ -alkyl aryl "or" C 1 -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ alkenyl aryl "," C ₂ -C ₆ -alkyl " _s -alkenyl heteroaryl "," C ₂ -C 6 -alkynyl aryl "," C ₂ -C ₆ -alkynyl heteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C 1 -C ₆ -alkyl heterocycloalkyl ".

"C 1 -C ₆ -alkyl acyloxy" means C 1 -C ₆ -alkyl groups having an acyloxy substituent, including 2- (acetyloxy) ethyl and the like.

"Alkoxy" means the group -OR where R includes _{"Ci-Ce-alkyl",} "C ₂ -C ₆ -alkenyl", "C ₂ -C 6 alkinyr," _{C3-C8-cycloalkyl} "," heterocycloalkyl ""aryl," heteroaryl "," CvCe-alkyl aryl "or" _Ci-C -alkyl heteroaryl "," C ₂ -C ₆ -alkenyl aryl "," C ₂ -C ₆ -alkenyl heteroaryl "," C ₂ - C ₆ -alkynyl aryl "," C ₂ -C ₆ -alkinylheteroaryl _"Ci-C6-alkyl cycloalkyl", _"Ci-C6-alkyl heterocycloalkyl".

"C 1 -C ₆ -alkyl alkoxy" means C 1 -C ₆ -alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like.

"Alkoxycarbonyl" means a -C (O) OR group wherein R comprises "C 1 -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C 6 -alkynyl", "C ₃ -C ₈ - cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," _Ci-C alkyl aryl "or" _Ci-C6-alkyl heteroaryl "," C ₂ -C ₆ -alkenyl aryl "," _C2 -C 6 -alkenyl heteroaryl "," C ₂ -C ₆ -alkynyl aryl "," C ₂ -C ₆ -alkynyl heteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C 1 -C ₆ -alkyl heterocycloalkyl ".

"C 1 -C ₅ -alkyl alkoxycarbonyl" means C 1 -C ₆ -alkyl groups having an alkoxycarbonyl substituent, including 2- (benzyloxycarbonyl) ethyl and the like.

"Aminocarbonyl" means -C (O) NRR ', wherein each R, R' independently includes hydrogen, "C 1 -C ₆ -alkyl", "C ₂ -C 6 -alkenyl", "C ₂ -C ₆ -alkynyl""C ₃ -C ₈ -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", _"Ci-C6-alkyl aryl" or "Ci-C _alkyl heteroaryl", "C ₂ -C ₆ -alkenyl aryl "," C ₂ -C ₆ -alkenyl heteroaryl "," C ₂ -C _s -alkynyl aryl "," C ₂ -C ₆ -alkinylheteroaryl "," _Ci-C6-alkyl cycloalkyl "," _Ci-C6 -alkyl heterocycloalkyl '.

"C 1 -C 6 -alkyl aminocarbonyl" means C 1 -C ₆ -alkyl groups having an aminocarbonyl substituent, including 2- (dimethylaminocarbonyl) ethyl and the like.

"Acylamino" means -NRC (O) R ', wherein each R, R' is independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl" , "C 3 -C 8 -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl," C 1 -C ₆ -alkyl aryl "or" C 1 -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ -alkenyl " aryl "," C ₂ -C ₆ -alkenyl heteroaryl "," C ₂ -C ₆ -alkynyl aryl "," C ₂ -C ₆ -alkynyl heteroaryl "," C ₁ -C ₆ -alkyl cycloacyl "," C 1 -C ₆ - alkyl heterocycloalkyl ".

"C 1 -C ₆ -alkyl acylamino" means C 1 -C ₆ -alkyl groups having an acylamino substituent, including 2- (propynylamino) ethyl and the like.

"Ureido" means -NRC (O) NR'R, wherein each R, R ', R is independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C _6" -alkynyl "," C ₃ -C ₈ -cycloalkyr, "heterocycloalkyl", "aryl", "heteroaryl", "C 1 -C ₆ -alkyl aryl" or "C 1 -C ₆ -alkyl heteroaryl", "C ₂ -C ₆ -alkyl" _6- alkenyl aryl "," C ₂ -C ₆ -alkenyl heteroaryl "," C ₂ -C ₅ -alkynyl aryl "," C ₂ -C ₆ -alkynyl heteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkynyl " -C ₆ -alkyl heterocycloalkyl ", and wherein R 1 and R 2 together with the nitrogen atom to which they are attached may optionally form a 3-8-membered heterocycloalkyl ring.

"C 1 -C ₆ -alkyl ureido" means C 1 -C ₆ -alkyl groups having an ureido substituent, including 2- (N'-methylureido) ethyl and the like.

"Carbamate means an -NRC (O) OR 'group wherein each R, R' is independently hydrogen," C ₁ -C ₆ -alkyl "," C ₂ -C ₆ -alkenyl "," C ₂ -C ₆ -alkynyl ", _{"C3-C8-cycloalkyl",} "heterocycloalkyl", "aryl", "heteroaryl", _"Ci-C6-alkyl aryl" or _"Ci-Ce-alkyl heteroaryl", "C ₂ -C ₆ -alkenyl aryl "," C ₂ -C _s -aIkenyl heteroaryl "," C ₂ -C ₆ -alkynyl aryl "," C ₂ -C _s -alkinylheteroaryl "," _Ci-C6-alkyl cycloalkyl "," _Ci-C6 - alkyl heterocycloalkyl ".

- 11 "Amino" means a group -NRR ', wherein each R, R' is independently hydrogen, "C 1 -C ₆ alkyl", "C ₂ -C 6 -alkenyl", "C ₂ -C ₆ -alkynyl", "C 3" -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C 1 -C ₆ -alkyl aryl "or" C 1 -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ alkenyl aryl, "C ₂ -C ₆ -alkenyl heteroaryl, "C ₂ -C ₆ -alkynyl aryl", "C ₂ -C ₆ -alkinylheteroaryl", _"Ci-C6-alkyl cycloalkyl", _"Ci-Ce-alkyl heterocycloalkyl", and wherein R and R 'together with the nitrogen atom to which they are attached may optionally form a 3- to 8-membered heterocycloalkyl ring.

"C 1 -C ₆ -alkyl amino" means C 1 -C ₆ -alkyl groups having an amino substituent, including 2- (1-pyrrolidinyl) ethyl and the like.

"Ammonium" means a positively charged group -N ⁺ RR'R '', wherein each R, R ', R is independently "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C _6" -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl, "C 1 -C 6 -alkyl aryl or" C 1 -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ alkenylaryl "," C ₂ -C ₆ - alkenylheteroaryl "," C ₂ -C ₆ -alkynyl aryl "," C ₂ -C ₆ -alkynyl heteroaryl "," C 1 -C ₆ -alkylcycloalkyl "," C 1 -C ₆ -alkylheterocycloalkyl ", and wherein R and R 'together with the nitrogen atom to which they are attached may optionally form a 3-8 membered heterocycloalkyl ring.

"C 1 -C ₆ -alkyl ammonium" means C 1 -C ₆ -alkyl groups having an ammonium substituent, including 2- (1-pyrrolidinyl) ethyl and the like.

"Ionizable residue" means a residue that can be converted into a salt, for example by protonation, amino or sulfonyl residues are examples of ionizable / protonizable residues.

"Halogen" means fluorine, chlorine, bromine or iodine atoms.

"Sulfonyloxy" means a -OSO ₂ -R group wherein R is selected from H, "C 1 -C ₆ -alkyl", "C ₁ -C ₆ -alkyl", substituted with halogens, for example -OSO 2 -CF 3, "C ₂ -C ₆ - alkenyl "," C 2 -C ₆ -alkynyl "," C ₃ -C 8 -cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C 1 -C ₆ -alkylaryl "or" C 1 -C ₆ -alkyl heteroaryl ", "C ₂ -C ₆ -alkenyl aryl", "C ₂ -C ₆ -alkenylheteroaryr", "C ₂ -C ₆ -alkynyl aryl", "C ₂ -C ₆ -alkynyl heteroaryl", "C ₁ -C ₆ -alkylcycloalkyl", "C ₁ -C ₆ -alkynyl" -C ₆ -alkylheterocycloalkyl ".

"C 1 -C ₆ -alkylsulfonyl" means C 1 -C ₆ -alkyl groups having a sulfonyloxy substituent, including 2- (methylsulfonyloxy) ethyl and the like.

"Sulfonyl" means the radical ,, - SO ₂ -R 'wherein R is selected H, "aryl", "heteroaryl", "Ci-Cs-alkyl", _"Ci-C -alkyl" substituted with halogens, e.g., a group -SO ₂ -CF ₃ , "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ -C ₈ -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", " Ci-Ce-alkyl aryl "or" _{Ci-C6-alkylheteroaryl,} "" C ₂ -C -alkenyl "," C ₂ -C ₆ -alkenylheteroaryl "," C ₂ -C _s -alkinylaryl "C ₂ -C ₆ - alkynyl heteroaryl "," C 1 -C ₆ -alkylcycloalkyl "," C 1 -C ₆ -alkylheterocycloalkyl ".

"C 1 -C 8 -alkylsulfonyl" means C 1 -C 6 -alkyl groups having a sulfonyl substituent, including 2- (methylsulfonyl) ethyl and the like.

"Sulfinyl ,, represents a group - S (O) -R wherein R is selected from H," _Ci-C alkyl "," _Ci-C6-alkyl "substituted with halogens e.g. an -SO-CF3 group," C ₂ -C ₆ alkenyl "," C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C ₁ -C ₆ -alkyllaryr "or" C ₁ -C ₆ -alkyl " -alkylheteroaryl "," C ₂ -C ₆ -alkenylaryl "," C ₂ -C ₆ -alkenylheteroaryl "," C ₂ -C ₅ -alkylaryl "," C ₂ -C ₅ -alkynyl heteroaryl "," C ₁ -C ₆ -alkylcycloalkyl ""," C 1 -C ₆ -alkylheterocycloalkyr. "

"C 1 -C ₆ -alkylsulfinyl" means C 1 -C ₆ -alkyl groups having a sulfinyl substituent, including 2- (methylsulfonyl) ethyl and the like.

13 "Sulfanyl" means -SR groups, wherein R comprises H, "C 1 -C 6 -alkyl", "C 1 -C ₆ -alkyl", substituted with halogens, for example -SO-CF ₃ , "C ₂ -C ₆ -alkenyl""C2-C6-alkynyl",_{"C3-C8-cycloalkyl",}"heterocycloalkyl","aryl","heteroaryl",_"Ci-Calkylaryl" or _{"Ci-C6-alkylheteroaryl,"} "C2 _C6 -alkenylaryr, "C ₂ -C ₆ -alkenyl heteroaryl", "C ₂ -C ₆ -alkinylaryl", _"C2-C6 -alkinylheteroaryl", _"Ci-C6-alkyl cycloalkyl", _"Ci-C6 - alkylheterocycloalkyl '. Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl and the like.

_"Ci-C -alkylsulfanyl" refers to the group _Ci-C6-alkyl groups having a sulfanyl substituent, including 2- (ethylsulfanyl) ethyl and the like.

"Sulfonylamino" means a group -NRSO ₂ -R ', wherein each R, R' includes independently hydrogen, "C 1 -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ -C _s cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C-Ce-alkyl aryl" or _"Ci-C6 alkyl heteroaryl", _"Ci-C6 -Alkenylaryl", _{"C2 C6} -alkenylheteroaryl "," C ₂ -C ₆ -alkynyl aryl "," C ₂ -C ₆ -alkinylheteroaryr, _"Ci-C6 -alkylcykloalkyi", _"Ci-C6 -alkylheterocykloalkyl".

"C 1 -C 6 -alkylsulfonylamino" means C 1 -C ₆ -alkyl groups having a sulfonylamino substituent, including 2- (ethylsulfonylamino) ethyl and the like.

"Aminosulfonyl means a -SO ₂ -NRR 'group wherein R, R' includes independently hydrogen," C ₁ -C ₆ -alkyl "," C ₂ -C 6 -alkenyl "," C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," alkyl "," heteroaryl "," _Ci-C6 alkylaryl "or" _{Ci-C6-alkylheteroaryl,} "" C ₂ -C _e -Alkenylaryl "," C2 _C6 -alkenylheteroaryl "," C ₂ -C ₅ -alkinylaryl "," C ₂ -C ₆ -alkinylheteroaryl "," _Ci-C6 -alkylcycloalkyl "," _C-C -alkylheterocykloalkyl ".

- 14 • · · * 9 9 9 9 99 φ

9 99 9 9 9

"C 1 -C ₆ -alkylaminosulfonyl" refers to C 1 -C ₆ -alkyl groups having an aminosulfonyl substituent, including 2- (cyclohexylaminosulfonyl) ethyl and the like.

"Substituted or unsubstituted": Unless otherwise defined by the definition of an individual substituent, the above groups such as "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl" and other groups may be substituted with 1 to 5 substituents selected from the group consisting of _{"Ci-C6-alkyl",} "C ₂ -C 6 -alkenyl", "C ₂ -C _s alkynyl", "cycloalkyl", "heterocycloalkyl", _"Ci-C6 alkylaryl""C 1 -C ₆ -alkylheteroaryl", "C 1 -C ₆ -alkylcycloalkyl", "C 1 -C ₆ -alkylheterocycloalkyl", "amino", "ammonium", "acyl", "acyloxy", acylamino "," aminocarbonyl "," alkoxycarbonyl "," ureido "," carbamate "," aryl "," heteroaryl "," sulfinyl "," sulfonyl "," alkoxy "," sulfanyl "," halogen "," carboxy ", trihalomethyl, cyano, hydroxy , mercapto, nitro and the like. Alternatively, said substitutions could also include situations where adjacent substituents have undergone ring closure, especially when they include adjacent functional substituents, i.e. they include, for example, lactams, lactones, cyclic anhydrides, but also acetal, thioacetals, aminals formed by ring closure, e.g. group.

"Pharmaceutically acceptable salts or complexes" means salts or complexes of the compounds of the following formula which retain the desired biological activity. Examples of such salts include, but are not limited to, inorganic acid addition salts (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like) and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid and polygalacturonic acid. Said compounds may also be administered as pharmaceutically acceptable in a quarter. salts, known

One skilled in the art, which specifically include quaternary ammonium salts of the formula -NR, R ', R ⁺ Z, wherein R, R', R is independently hydrogen, alkyl or benzyl, C 1 -C ₆ alkyl, C ₂ -C 6 -alkenyl C ₂ -C ₆ -alkynyl, C, -C _s -alkylaryi, C ₅ -alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate , phosphate or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandloate and diphenylacetate).

A "pharmaceutically active derivative" refers to any compound which, when administered to a recipient, is capable of exerting a directly or indirectly described effect.

"Enantiomeric excess" (ee) means products that are obtained by asymmetric synthesis, for example by synthesis involving non-racemic starting materials and / or reagents, or by a synthesis comprising at least one enantioselective step, resulting in an enantiomeric excess of at least 52%. The absence of asymmetric synthesis usually results in racemic products which, however, also act as OT-R antagonists.

The general formula (I) of the present invention also includes tautomers, geometric isomers, optically active forms such as enantiomers, diastereomers, and racemate forms as well as pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts of formula (I) are acid addition salts formed with pharmaceutically acceptable acids such as hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate salts , gluconate, methanesulfonate, benzenesulfonate and para-toluenesulfonate.

One aspect of the present invention consists of pyrrolidine oxadiazole and thiadiazole compounds of formula (I).

- 16 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The pyrrolidine oxadiazole and thiadiazole derivatives of formula (I) are suitable for modulation, particularly for inhibiting OT-R function, and more specifically for antagonizing the oxytocin receptor. When the oxytocin receptor is bound by the compounds of formula (I), oxytocin is antagonized so that it is blocked from its receptor and is therefore unable to exert its biolobic and pharmacological effects. The compounds of the present invention are therefore particularly suitable for the treatment and / or prevention of oxytocin-related diseases in mammals and especially humans.

The compounds of the present invention are compounds of formula (I).

The formula also includes its geometric isomers, optically active forms such as enantiomers, diastereomers, and its racemate forms as well as its pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts of compounds (I) are acid addition salts formed with pharmaceutically acceptable acids such as hydrochloride, hydrobromide, sulfate, bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate,

- 17 * · c · c · maleate, lactate, citrate, tartrate, gluconate, methanesulfonate (mesylate), benzenesulfonate and para-toluenesulfonate.

In said formula (I), the group A is selected from the group consisting of - (C = O) -, - (C = O) -O-, -SO ₂ -, -SO ₂ NH-, -C (= NH) -, - (C = O) -NH-, - (C = S) -NH, -ch ₂ -. Most preferably, A is a carbonyl group.

B is an unsubstituted or substituted thiadiazole ring.

R ¹ is selected from the group consisting of or consisting of unsubstituted C 1 -C 6 -alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C 1 -C 6 -alkylaryl, unsubstituted or substituted C 1 -C 6 -alkyl heteroaryl, R ¹ may form, with the O atom to which it is attached, a 3- to 8-membered substituted or unsubstituted, saturated or unsaturated heterocyclic ring which may contain 1 to 2 further heteroatoms selected from N, S and O, and which is optionally linked to an aryl, heteroaryl or 3- to 8-membered saturated or unsaturated cycloalkyl ring. Preferably R ¹ is H or C 1 -C 3 -alkyl, most preferably methyl.

R ² is selected from the group comprising or consisting of unsubstituted or substituted _Ci-C6 alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted aryl , unsubstituted or substituted heteroaryl groups, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, acyl groups, unsubstituted or substituted C 1 -C ₆ -alkyl aryl, unsubstituted or substituted C 1 -C ₆ -alkyl heteroaryl groups , said cycloalkyl or aryl or heteroaryl groups may be combined with 1-2 other cycloalkyl or aryl or heteroaryl groups. More preferred is an aryl group, especially a phenyl group, which is optionally substituted, for example, with another group (i.e., forming a biphenyl residue).

R ^3, R ^4, R ⁵ and R ⁶ are independently selected from the group consisting of the group hydrogen, halogen, _Ci-C6 alkyl, _Ci-C alkoxy. Preferably each is H.

Preferred pyrrolidine derivatives are compounds of formula (I) wherein R ¹ is selected from the group consisting of H or -C 1 -C ₆ alkyl, especially -CH ₃ , A is - (C = O) -, R ² is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, especially biphenyl.

According to a preferred embodiment, substituent B is a 1,2,4 oxadiazole substituent which may be attached to the pyrrolidine ring by the following methods (IIa) or (Nb):

(Hb)

In said formulas (IIa) and (IIb), R ^{7 is} selected from the group consisting of or consisting of hydrogen, sulfonyl, amino, unsubstituted or substituted C 1 -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl groups unsubstituted or substituted C ₂ -C ₆ alkynyl wherein said alkyl chain, alkenyl can be interrupted by heteroatoms selected from N, O or S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3 to 8- 19 -

membered cycloalkyl, unsubstituted or substituted heterocycloalkyl groups, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be linked to 1-2 additional cycloalkyl, heterocycloalkyl, aryl heteroaryl, acyl radicals, unsubstituted or substituted (C 1 -C 6 -alkyl aryl) groups , unsubstituted or substituted _Cl-C6-alkyl heteroaryl, unsubstituted or substituted C ₅ -C ₆ -alkenyl aryl, unsubstituted or substituted _{Cl-C6-alkenyl} heteroaryl, unsubstituted or substituted _Ci-6 -alkynyl aryl, unsubstituted or substituted C 1 -C ₆ -alkynyl heteroaryl, unsubstituted or substituted C 1 -C ₆ -alkyl cycloalkyl groups, unsubstituted or substituted C 1 -C ₆ -alkyl heterocycloalkyl groups, unsubstituted or substituted C 1 -C ₆ -alkenyl cycloalkyl groups, unsubstituted or substituted groups C 1 -C ₆ -alkenyl heterocycloalkyl, unsubstituted unsubstituted or substituted C 1 -C ₆ -alkynyl heterocycloalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted C 1 -C ₆ -alkyl carboxy, substituted or unsubstituted C 1 -C ₆ -alkyl acyl groups, substituted or unsubstituted aryl, acyl groups, substituted or unsubstituted heteroaryl acyl groups, substituted or unsubstituted C ₃ -C ₈ - (hetero) cycloalkyl acyl groups, unsubstituted or substituted C 1 -C ₆ -alkyl groups acyloxy, unsubstituted or substituted _Ci-C6-alkyl alkoxy, unsubstituted or substituted _Ci-C -alkyl alkoxycarbonyl, unsubstituted or substituted _Ci-C-alkyl aminocarbonyl, unsubstituted or substituted _Ci-C6-alkyl acylamino, acylamino, unsubstituted or substituted groups C 1 -C ₆ -alkyl ureido, substituted or unsubstituted C ₆ -C ₆ -alkyl carbamate, unsubstituted or substituted C 1 -C ₆ -alkyl amino, unsubstituted or substituted C 1 -C ₆ -alkyl ammonium, unsubstituted or substituted C 1 -C ₆ -alkyl sulfonyloxy groups unsubstituted or substituted C ^ Ce-alkyl sulfonyl, unsubstituted or substituted _Ci-C6-alkyl sulfinyl, nesubstituo- 20 blows or substituted Cl-C6-alkyl sulfanyl, unsubstituted or substituted _Ci-C6-alkyl sulfonylamino, unsubstituted or substituted _C 1 -C ₆ -alkyl aminosulfonyl, hydroxy, halogen, cyano.

According to a preferred embodiment, R ⁷ is a substituent containing an ionizable residue (particularly protonizable).

In particular, R ⁷ may be selected from the group consisting of carboxy or amino residues.

Alternatively, R ⁷ may be selected from the group consisting of any of the above substituents having at least one carboxy or amino radical. A preferred ionizable moiety is a cyclic tertiary amine (heterocycloalkyl).

More preferred are C 1 -C ₆ -alkyl amino, heterocycloalkyl such as piperazines or piperidines, C 1 -C 6 -alkyl heterocycloalkyl, aminocarbonyl, C 1 -C ₆ -alkyl aminocarbonyl, C 1 -C ₆ -alkyl acylamino, C 1 -C ₆ -alkyl sulfonyl, C 1 -C ₆ -alkyl carboxy.

Most preferred are dimethylaminomethyl, 2- (dimethylamino) ethyl, 1-methyl-3-piperidinyl, (4-acetyl-1-piperazinyl) -methyl.

In another embodiment, substituent B is a 1,3,4-oxadiazole of formula (IV) or a tautomer of formula (III):

(iv)

• · a a * * * a * * a * a

In said formulas (III) and (IV), X is O or S, wherein in the case of formula (IV) X may also be a bond. In the case where X is O or S and R ₈ is hydrogen, the compounds of formula (IV) represent the corresponding tautomers of formula (III).

_And R of formula (IV) is chosen from the group comprising or consisting of hydrogen, unsubstituted or substituted _Ci-Ce alkyl, unsubstituted or substituted C ₂ -C _s alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkines [, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl groups, unsubstituted or substituted saturated or unsaturated 3 to 8 membered cycloalkyl groups, optionally containing at least one heteroatom (for example 1 to 3), selected from N, O, S, acyl radicals , unsubstituted or substituted C 1 -C ₆ -alkyl aryl groups, unsubstituted or substituted C 1 -C ₆ -alkyl heteroaryl groups, unsubstituted or substituted C 1 -C ₆ -alkenyl aryl groups, unsubstituted or substituted C ₆ -C ₆ -alkenyl heteroaryl groups, substituted or unsubstituted alkoxycarbonyl, carboxylic amide, substituted or unsubstituted groups C 1 -C ₆ -alkoxy, substituted or unsubstituted aryloxy groups, substituted or unsubstituted heteroaryloxy, halogen, cyano, substituted or unsubstituted C 1 -C ₆ -alkyl carbonyl groups, substituted or unsubstituted aryloxycarbonyl or heteroarylcarbonyl groups, substituted or unsubstituted saturated or unsaturated groups C 4 -C ₈ -cycloalkylkarbonyl, said cycloalkyl group or aryl or heteroaryl groups may be linked with 1-2 further cycloalkyl or aryl or heteroaryl, and wherein said chain alkyl, alkenyl and alkynyl can be interrupted by heteroatoms selected from N, O or s .

Particularly preferred pyrrolidine derivatives are compounds of formula (I) wherein A is - (C = O), R ¹ is C 1 -C ₆ alkyl, R ² is either aryl or heteroaryl, each of R ³ , R ⁴ , R ⁵ and R ⁶ are H and B is oxadiazole of formula (IIa), (IIb), (III) or (IV).

The most preferred pyrrolidine derivatives are compounds of formula (I) wherein A is - (C = O), R ¹ is a methyl group, R ² is either (un) substituted aryl or

- a (un) substituted heteroaryl group, wherein each of R ³ , R ⁴ , R ⁵ and R ⁶ is H and B is an oxadiazole of formula (11a), (IIb), (III) and (IV), especially 1,2 4 oxadiazole of formula (IIa) or (IIb).

Most preferred pyrrolidine derivatives are compounds of formula (I), A is - (C = O), R ¹ is methyl, R ² is biphenyl, each of R ³ , R ⁴ , R ⁵ and R ⁶ is H and B is oxadiazole of formula (IIa), (IIb), (III) and (IV), in particular 1,2,4 oxadiazole of formula (IIa) or (IIb).

The compounds of formula (I) may contain one or more asymmetric centers and may therefore exist as enantiomers or diastereoisomers. It is to be understood that the invention encompasses both mixtures and separately the individual isomers or enantiomers of the compounds of formula (I). In a particularly preferred embodiment, the pyrrolidine derivatives of formula (I) are obtained in an enantiomeric excess of at least 52% ee, preferably at least 92-98% ee.

Specific examples of compounds of formula (I) include the following compounds:

(3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) ) -1 - [(2'-methyl- [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime ( 3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (1,3,4-oxadiazol-2-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) - 1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-oxo-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1- ( [1,1'-biphenyl] -4-ylcarbonyl) -5- (5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) - 5- (3-Benzyl-1,2,4-oxadiazol-5-yl) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime

23 (3'Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (3 - {[(2-furylmethyl) sulfanyl] methyl} 1,2,4-oxadiazole-5 -yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3- [2-oxo-2- (1-pyrrolidinyl) ethyl] ethyl ] 1,2,4-Oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3R, 5S) -1 - ([1, T-biphenyl] -4-ylcarbonyl) -5- {3 - [(2 -pyridinylsulfanyl) methyl] 1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1, T-biphenyl] -4-ylcarbonyl) -5- [3- ( 4-fluorophenyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3- [ (2-thienylsulfanyl) methyl] -1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3- [2- (3,5-Dimethyl-1H-pyrazol-1-yl) -ethyl] -1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(methylsulfonyl) methyl] -1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (5-methyl-3-isoxazolyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- [3- (2-thienylmethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- (3-phenyl-1,2,2-oxadiazol-5-yl) -3-pyrrolidinone O -methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (3 - {[(2-furylmethyl) sulfonyl] methyl} 1,2,4-oxadiazol-5-yl -3-Pyrrolidinone O-methyloxime (3ZZ, 5S) -5- [3- (aminomethyl) -1,2,4-oxadiazol-5-yl] -1 - ([1,1-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime

(3EZ, 5S) -1 - ([1,1'-biphenylH-ylcarbonyl] -5- (5S-nRS) -hydroxyphphenylmethyl] 1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(1S, 5S) -1-hydroxypropyl] -1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O- (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (hydroxymethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(1S, 2R) -2-hydroxycyclohexyl] 1,2,4-oxadiazol-5-yl -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazole-5- yl] -3-pyrrolidinone O-methyloxime (3Z, 5RS) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazole-5- yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (4-piperidinyl) -1,2,4-oxadiazole -5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(3S) -piperidinyl] -1 2,4-Oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(2S)] -piperidinyl] -1,2 4-Oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - [(2'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl- 1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -1 - {[2'- (trifluoromethyl) [1,1'-biphenyl] -4-yl] carbonyl} -3-pyrrolidinone O-methyloxime (3Z, 5S) -1 - [(2'-fluoro [1,1'-biphenyl] -4-yl) (carbonyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime

- 25 (3EZ, 5S) -1 - [(4'-Fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) - 3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (1,2,4-oxadiazole-3- yl) -3-pyrrolidinone O-methyloxime (3E, 5S) -1 - [(2'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2, 4-Oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3E, 5S) -1 - [(2'-methyl [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl- 1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3Z, 5S) -1 - [(2'-methyl [1,1'-biphenyl] -4-yl) carbonyl] -5- ( 3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- ( phenoxymethyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-phenyl- 1,2,4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime N - ({3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4 - (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazol-5-yl} methyl) acetamide (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5- [4- (hydroxymethyl) phenyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (2-hydroxyethyl) -1,2,4-oxadiazol-3-yl] -3- pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(2S) -2-hydroxy-2-phenylethyl] 1,2,4-oxadiazole -3-yl} -3-pyrrolidinone O-methyloxime {3 - [(2S, 4EZ) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazole -5-yl} methylformamide · form form form form form form methyl methyl methyl methyl methyl form form form--methyl methyl methyl form form · ····· ··

26 (3'Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (methoxymethyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3R, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (2-phenoxyethyl) -1,2,4-oxadiazol-3yl] - 3-pyrrolidinone O-methyloxime (3R, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (2-methoxyethyl) -1,2,4-oxadiazol-3-yl] 3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- [5- (1-acetyl-4-piperidinyl) -1,2,4-oxadiazol-3-yl] -1 - ([1,1 '] -biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (2-pyridinyl) -1,2] 4-oxadiazol-3-yl] 3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (3-th Phenyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3'Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-methylpyridine) ethyl-1,2,4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-cyclopentyl- 1,2,4-oxadiazol-3-yl) 3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-methyl-1; 2,4-Oxadiazol-3-yl) -3-pyrrolidinone O-methylox im (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(ES) -hydroxy (phenyl) methyl] -1,2,4-oxadiazol-3-yl -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(1RS) -1-hydroxy-2-phenylethyl] 1 2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(1 R) -1- (dimethylamino) -2-phenylethyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime

27 (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (3-pyridinyl) -1,2,4-oxadiazol-3-yl] 3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (4-pyridinyl) -1,2,4-oxadiazol-3-yl] 3 -pyrrolidinone O-methyloxime (3Z, 5S) -5- {5 - [(4-acetyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-3-yl} -1 - ([1,1-biphenyl] 4-ylcarbonyl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- [3- (1-acetyl-4-piperidinyl) -1,2,4-oxadiazol-5-yl] -1- ( [1,1'-Biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- {5 - [(4-acetyl-1-piperazinyl) methyl] -1,2,4-oxadiazole -3-yl} -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime

A / - ({3 - [(2S, 4 £ Z) -1 - ^{([1.1-biphenyl]} - 4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5 (yl) methyl) -3- (1-piperidinyl) propanamide (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(3S) -1-methylpiperidinyl] -1,2,4oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(3E) -1-methylpiperidinyl] -1,2,4oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [ 5- (6-hydroxy-3-pyridinyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) ) -5- {5 - [(dimethylamino) methyl] -1,2,4oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- {5 - [(1S, 2R) -1-amino-2-hydroxypropyl] -1,2,4-oxadiazol-3-yl} -1 ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(3S) -piperidinyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime

(3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- {5 - [(3R) -piperidinyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5RS) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (1-methyl-3-piperidinyl) -1,2,4-oxadiazol-3-yl] 3-pyrrolidinone O-methyloxime tert-butyl- (3E) -3- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} -1-piperidinecarboxylate

4- ({3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazol-5-yl} methyl) -2,6-piperazinedione (3Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3Z, 5S) -1 - [(2'-chloro-4'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1) 2,4-Oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3R, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (1-methyl) -4-piperidinyl) -1,2,4oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- { 5 - [(dimethylamino) methyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5 - [3- (1-methyl-4-piperidinyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- {5 - [(1S) -1-amino -2-hydroxyethyl] -1,2,4-oxadiazol-3-yl} -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime

5 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] - N - [3 (dimethylamino) propyl] -1,2,4 oxadiazole-3-carboxamide (3E, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(dimethylamino) methyl] -1,2,4oxadiazol-3-yl 3-Pyrrolidinone O-methyloxime

- 29 • t-butyl- (3S) -3- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} -1-piperidinecarboxylate (3EZ, 5S) -1- ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(4-methyl-1-piperazinyl) methyl] 1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime ( 3Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(4-methyl-1-piperazinyl) methyl] 1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime ethyl-5 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazole-3- (3E, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone carboxylate O -methyloxim / V-({3-[(2S,4EZ)-1-([1,1'- biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]1.2.4- oxadiazol-5-yl} methyl) -3- (dimethylamino) propanamide tert-butyl 4- (2- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} ethyl) -1-piperazinecarboxylate (3EZ, 5S) -1 - [(2'- chloro-4'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - [(4'-Fluoro-2'-methyl- [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5- [2- (dimethylamino) ethyl] -1,2, 4-Oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime

2- {5 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazol-3-yl} ethyl [(ferf -butoxycarbonyl) amino] acetate / N-({3-[(2S,4EZ)-1-([1,1'- biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]1.2.4- oxadiazole- 5-yl} methyl) -2- (dimethylamino) acetamide

- 30 · · · 30 30 - 30 · 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 (3EZ, 5S) -1 - [(2'-chloro-4'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2), 4-Oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- {5 - [(1S) -1-amino-2-tert-butoxyethyl] -1,2,4-oxadiazole-3- yl} -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime tert -butyl 4- {5 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] 4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-3-yl} -1-piperidinecarboxylate (3EZ, 5S) -1 - ([1,1'-biphenyl] -4- ylcarbonyl) -5- [5- (1-piperazinylmethyl) -1,2,4oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime tert-butyl (4S) -4- {3 - [(2S, 4EZ) ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} -4 - [(tert -butoxycarbonyl) amino] butanoate

4 - {[(2S, 4EZ) -2- (5 - {[(tert-butoxycarbonyl) amino] methyl} -1,2,4-oxadiazol-3-yl) 4- (methoxyimino) pyrrolidinyl] carbonyl} -1 1'-biphenyl tert-butyl 2- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4 -oxadiazol-5-yl} ethylcarbamate

2- {5 - [(2S, 4EZ) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazol-3-yl} ethyl aminoacetate (3E, 5S) -1 - [(2 ', 4'-difluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3- pyrrolidinone O-methyloxime (3EZ, 5S) -1 - [(2 ', 4'-difluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4oxadiazole- 5-yl) -3-pyrrolidinone O-methyloxime

4 - {[(2S, 4EZ) -2- (5 - {(1S) -2-tert-butoxy-1 - [(tert-butoxycarbonyl) amino] ethyl} 1,2,4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl] carbonyl} -1, Γ-biphenyl (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-vinyl-1,2, 4-Oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime

- 31 · 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 ·· · · · · · ·

4 - {[(2S, 4EZ) -2- (5 - {(1S, 2R) -2-tert-butoxy-1 - [(tert-butoxycarbonyl) amino] propyl} -1,2,4-oxadiazole-3 -yl) -4- (methoxyimino) pyrrolidinyl] carbonyl} -1,1-biphenyl (3Z, 5S) -1 - [(2 ', 4'-difluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4oxadiazol-5-yl) -3-pyrrolidinone tert -butyl 4 - ({3 - [(2S, 4EZ) -1 - ([1,1'- biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} methyl) -1-piperazinecarboxylate

Another aspect of the present invention relates to the use of the pyrrolidine oxadiazole or -thiadiazole derivatives of formula (I) as a medicament, in particular for the treatment and / or prevention of premature labor, premature labor, cessation of delivery before caesarean section and painful menstruation. Preferably, the compounds of formula (I) are suitable for modulating OT function, therefore specifically allowing treatment and / or prevention of disorders caused by the oxytocin receptor. Said treatment allows modulation - particularly regulation or antagonization - of the oxytocin receptor.

More specifically, the compounds of the present invention are useful for the treatment of preterm labor, painful menstruation, and for stopping labor before caesarean section.

Yet another object of the present invention is a process for the preparation of pyrrolidine derivatives according to formula (I).

The pyrrolidine derivatives exemplified herein can be prepared from commonly available starting materials using the following general methods and procedures. It will be appreciated that where conventional or preferred experimental conditions (e.g., temperatures, time, moles of reagents, solutions, etc.) are given, other experimental conditions may be used unless otherwise stated. Optimal reaction conditions may vary with particular

- 32 · ········ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Reagents or solvents used, but these conditions can be determined by one skilled in the art by routine optimization procedures.

In general, the pyrrolidine derivatives of formula (I) could be obtained in several ways using dissolved phase and solid phase chemistry protocols.

In one method, the pyrrolidine derivatives of formula (I) wherein B is 1,2,4 oxadiazole of formula (IIa) are prepared from the corresponding carboxylic acid compounds (V) and amidoximes (VI), wherein R ¹ R ⁷ and A are defined above, using known liquid phase chemistry protocols, such as the method set forth in the examples and shown in Scheme 1 below.

Scheme 1

The amidoxime compounds (VI) are either obtained from industrial sources or made from the corresponding nitriles (VII) by reacting them with hydroxylamine under standard conditions well known to one skilled in the art, such as those described in the examples and depicted in the examples. diagram 2 below.

Scheme 2

HIM.

H ₂ N r ⁷

VII

VI

- 33 · 9 9 9 9 9 9 9 · * * * * * * * * * * * * * * * * * * * * · · · ·

The nitrile compounds VII are obtained either from industrial sources or are prepared, for example, from the corresponding carboxylic acids (VIII) as shown in Scheme 3, by carrying out one of the functional group interconversion methods well known to one skilled in the art. converting the carboxylic acid into the corresponding nitrile. Examples include (i) reduction of the carboxylic acid (VIIIa) to the corresponding carbaldehyde followed by transformation to the corresponding oxime and dehydration of the latter to the corresponding nitrile (VII) using, for example, Λ /, Λ / - carbonyldiimidazole or similar reagents, or (ii) transforming the carboxylic acid (VIII) into the corresponding primary carboxamide followed by dehydration to the corresponding nitrile (VII), using standard conditions well known to one skilled in the art, as described in the Examples below.

Scheme 3

HIM

Vlil

VII

Pyrrolidine-2-carboxylic acids (V) (see Scheme 1), wherein R ^1, R ⁷ and A are as defined above, can be prepared from compounds of formula (IX) by reaction with substituted hydroxylamines (X) with using standard synthesis techniques, which are further described in the examples and shown in Scheme 4.

- 34 * 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34

Scheme 4

Compounds of formula (X) are obtained either from industrial sources or are prepared from N-Boc-hydroxylamine (XI) and alkylating agents (XII) (X = Cl, Br, I) by standard synthesis routes as shown in Scheme 5; and described below in the examples.

Scheme 5

XI XII x

The keto compounds of formula (IX) wherein R ¹ -R ⁷ and A are as defined above may be prepared by oxidizing commercially available, suitably N-protected 4-hydroxyproline (XIII) using standard techniques Alternatively, compounds of formula (IX) alone can be obtained from compounds of formula (V) by transforming the oxime ether to a ketone residue, for example under conditions of poor hydrolysis, as described in the examples below. If in this case the ketone compounds (IX)

subsequently reacting with another hydroxylamine compound X * as shown in Scheme 6, then the entire transformation of V ¹ X ¹ → V 1 will correspond to the interchange of R ¹ in the oxime ether residue of the compounds of formula (V). Analogous oxime ether interconversion is possible at the level of the final compounds of formula (I) (I → XIV → I *). as also shown in Scheme 6.

Scheme 6

In another method, the pyrrolidine derivatives of formula (I) wherein B is 1,2,4 oxadiazole of formula (IIb) are prepared from the corresponding amidoxime acid compounds (XV), wherein R ¹ -R ⁷ and A are as defined in as described above, and the carboxylic acids (VIII) are produced by the process described above. · ···· ·· *

99 99 99

36 well-known dissolved phase chemistry protocols as described in the examples and shown in Scheme 7 below.

Scheme 7

Vlil

[B = lib]

The amidoxime compounds (XV) are obtained from the corresponding nitriles (XVI), wherein the substituents R ¹ -R ⁷ and A are defined as above by treating the latter with hadroxylamine under standard conditions well known to one skilled in the art as described in the examples and shown in Scheme 8 below. The nitrile compounds (XVI) themselves are prepared, for example, from the corresponding carboxylic acids (V), wherein the substituents R ¹ -R ⁷ and A are as defined above, by methods of interconversion of any functional group well known to those skilled in the art. to the corresponding nitrile. Examples include (i) reduction of the carboxylic acid (V) to the corresponding carbaldehyde followed by transformation to the corresponding oxime and dehydration of the latter to the corresponding nitrile (XVI) using, for example, Λ /, Λ / - carbonyldiimidazole or similar reagents, or (ii) transformation carboxylic acids (V) to the corresponding primary carboxamide and subsequent dehydration to the corresponding nitrile (XVI), using standard conditions well known to one skilled in the art, as described in the Examples below.

- 37 Diagram 8

The pyrrolidine derivatives of formula (I) wherein B is 1,3,4 oxadiazole of formula (III) and / or (IV) may be prepared from the corresponding hydrazide compounds (XVII), wherein R ¹ -R ⁷ and A are defined as above, dissolution phase chemistry protocols well known to those skilled in the art, which are described in the examples and shown in Scheme 9 below. For example, compounds of formula (I) wherein substituent B is 1,3,4 oxadiazole of formula (III) may be obtained by reacting compound (XVII) with CDI or CS ₂ , under basic conditions, to yield the corresponding products wherein X is O and or S. Alternatively, the hydrazide intermediates (XVII) can be reacted with TMOF followed by P ₂ O ₅ in refluxing toluene to give compounds of formula I wherein B is (IV).

- 38 Scheme 9 «» · «« «« «38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38

CDI (X = 0) or CS ₂ (X = S)

I [B = IIIa (X = O)] I [B = IIIb (X = S)]

The hydrazide compounds (XVII) are obtained, for example, from the corresponding carboxylic acids V, wherein the substituents R ¹ -R ⁷ and A are as defined above, using the corresponding methyl esters (XVIII) and subsequent reaction of the latter with hydrazine under standard conditions well known to a person skilled in the art. of the art, which are described in the examples and shown in Scheme 10 below.

- 39 Scheme 10

• r · · · · · · · · · · · · ·

Compounds of formula (I) wherein R ¹ -R ⁸ and A are as defined above are therefore available from the precursors of formula (V) / (XVIII) (see Scheme 1, 7-10 above). Typically, said precursors of formula (V) / (XVIII) initially have a nitrogen protecting group of a pyrrolidine ring, such as Boc, Fmoc or other, hence the designation (V) and / or (XVIII ') (-AR ² = protecting group , PG) as shown in Scheme 11. In the synthesis of the final compounds (I), the N-protecting groups (V ') and / or (XVIII') are usually removed and replaced with a suitable Λ / substituent such as an acyl group, a -C (O) -R ² or -SO ₂ -R ^{2 group} , for example by treatment with an acylating agent or a sulfonating agent (XX). Other compounds of formula (XX) are carboxylating agents, sulfonating agents, sulfonamidating agents, imidating agents, amidating agents, thioamidating agents, or alkylating agents. Coupling of the desired moiety (-AR ² ) to the pyrrolidine nitrogen atom may be carried out either after or before the formation of the oxadiazole or thiadiazole ring as shown in Scheme 11 (A and or B) and described further in the Examples below. The most suitable choice of sequential synthesis protocol will depend on the nature of the substituents R ¹ -R ⁸ (especially R ⁷ ). Preferred acylating agents (XX) are acid chlorides (XXa) usually used concomitantly with suitable tertiary amine bases or carboxylic acid (XXb) used concomitantly with a peptide binding agent, for example DIC or EDC.

- 40 • ·· φ φ φ φ · · · φ φ «

5 ·· Φ Φ Φ * * φ φ φ φ • • • • • • • • • · · ·

Compounds of formula (I) wherein A is - (C = O) -O-, -SO ₂ -, -SO ₂ NH -, - C (= NH) -, - (C = O) NH, - (C = S) -NH, -CH ₂ -, can be prepared using appropriately modified carboxylating agents, sulfonating agents, sulfonamide agents, imidating agents, amidating agents, thioamidating agents or alkylating agents, for example sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates, substituted alkyl halides or others, to form sulfonamide, urea, thiourea, carbamate, substituted alkyl derivatives, and others.

- 41 Diagram 11 9 <- 9

999 9 9 99 9 9 99 9

[-AR ² = PG ₁ e.g. Boe] (N protection removed)

-O. ^R5 .'Γ ^«R h

XIX

XXa (eg, A = C (O); LG = CI) XXb (eg, A = C (O); LG = OH)

Base or peptide binding agent (Scheme 1, 7-10)

[-AR ² = -PG, eg-Boc]

I [-A-R2 = -C (O) -R2] (Removal of protection N)

LG

XXa (eg A = C (O); LG = CI) XXb (e.g. A = C (O); LG = OH)

Base or peptide binding agent (Scheme 1, 7-10)

[-AR ² = -C (O) -R ² ]

According to another general process, compounds of formula (I) may be converted to alternative compounds of formula (I ') by appropriate techniques

Protected / unprotected / functional group conversions well known to those skilled in the art, as shown in Scheme 12 and described in the Examples below.

Scheme 12

[B = Ha, lib]

Where B 'is B substituted as above

[B ‘= lla ', lib']

Examples include:

1. Removing Protection N

1. Removing Protection N

2. Alkylation: R-CH3 / base (X = Cl, Br, I)

2. Acylation: R-COX / base (X = Cl, Br, OH)

R ‘

R ’

In yet another method, the pyrrolidine derivatives of formula (I) are prepared by a new solid phase protocol as shown in Scheme 13 and described in the Examples below. For example, in the solid phase synthesis of compounds of formula (I) wherein B = (IIa), the N -Boc-protected pyrrolidine derivative (V) is reacted with a resin that is prone to nucleophilic cleavage, such as Kaiser oxime resin, using standard carbodiimide-mediated coupling conditions well known to those skilled in the art. Removal of Boc protection with dilute TFA in DCM or BF ₃ .EEt ₂ in dilute HOAc in DCM affords compounds of formula (XXIV). The latter compound can be treated with acylating agents of formula (XX), wherein A and R ² are as defined above and LG could be a suitable leaving group. Preferred acylating agents (XX) are the acid chlorides (XXa) used concurrently with the tertiary amine base, or the carboxylic acids (XXb) used concomitantly with a peptide binding agent such as DIC, EDC, TBTU, DECP or others to form products of formula (XXIII). Compounds of formula (I) wherein A is different from the carbonyl function are prepared by replacing formula (XX) with compounds containing suitable functional groups such as sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates, substituted alkyl halides or others to form sulfonamide, urea, thiourea, carbamate, substituted alkyl derivatives and others. In order to obtain the final compounds of formula (I), the bond to the resin is cleaved by prolonged treatment with amidoximes (VI) followed by heating, for example with pyridine. The rings in Scheme 13 symbolize a bed of resin to which the corresponding compounds bind during solid phase synthesis. Other derivatives of formula (I) are prepared using known modifications or variations to the sequence of reactions in Scheme 13. For the solid phase synthesis of a compound of formula (I), other suitable reagents, in particular resins known to those skilled in the art, may be used in addition to the above Kaiser oxime resin. field.

• · ·················································

Scheme 13

R

ΧΧ1ΙΓ [-AR ² = -PG.noc.Boc]

Peptide Binding Agent

Removal of protection

ri ^rS 9

N. „R

XXIII '[-AR ² = -PG. Boc]

zA _{x 2}

LG R ²

XXa (eg, A = C (O) 1G = CI)

XXb (eg A = C (O) IG = OH)

Base or peptide binding agent? R ^S Q

XXIII [-AR ² = -C (O) -R 2]

[-A-R 2 = -C (O) -R ² ] ^h % h ₂ n R ⁷

VI

[-AR ² = -C (O) -R 2]

The sequence of reactions outlined in the above schemes provides enantiomerically pure compounds of formula (I) when enantiomerically pure starting compounds are used. The (R) - as well as the (S) -enantiomers can be obtained depending on whether (R) - or (S) - forms of the industrially available compounds of formulas (V) - (VIII), (X), were used as starting materials. ) and / or (XX).

However, the sequence of reactions outlined in the above schemes usually provides mixtures of (E) - and (Z) -isomers with respect to substituents on the exocyclic double bond of the pyrrolidine ring. In all cases studied, these (E) / (Z) -isomers could be separated by standard chromatographic techniques well known to those skilled in the art, such as reverse phase high pressure liquid chromatography (HPLC) or silica gel flash chromatography (FC). Alternatively, one of the (E) / (Z) -isomers could subsequently be enriched by selective crystallization in suitable solvents or solvent mixtures. The determination of the absolute configuration of the exocyclic double bond was performed using NMR techniques well described in the literature and known to those skilled in the art (for determining configurations of, for example, oxime groups, see, for example, E. Breitmaier, W. Voelter Carbon-13 NMR Spectroscopy, 3rd ed. VCH, 1987, p. 240). To increase the overall yields of the preferred isomer (usually (Z) isomer), the less preferred isomer (usually (E) isomer) could be recycled by arbitrary re-isomerization in organic solvents containing traces of acid, such as HCl, followed by re-separation ( E) / (Z) by chromatography and / or crystallization as shown in Scheme 14.

- 46 Diagram 14

A XVb ar ² Chromatography or crystallization R \ 0 1 ^N x \ tx N AR ² ₊ ° X ar ² l- (BZ) l- (E) l- (Z)

organic solvent, HCl (trace)

If the above general synthesis methods are not applicable to obtain compounds of formula (I) and / or the necessary intermediates for the synthesis of compounds of formula (I), suitable methods known to those skilled in the art could be used. In general, the method of synthesizing any single compound of formula (I) will depend on the specific substituents of each molecule and on the availability of the necessary intermediates; again, these factors are obvious to the person skilled in the art. For all ways of protecting, removing protection, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis", Wiiey- Interscience, 1991.

The compounds of the invention may be isolated together with solvent molecules by crystallization from evaporation of a suitable solvent. The pharmaceutically acceptable acid addition salts of the compounds of formula (I) which contain a basic center may be prepared in a conventional manner. For example, the free base solution may be treated with a suitable acid, either in pure form or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation of the reaction solvent in vacuo. Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of the compound of formula (I)

acting in a suitable manner. Both types of salt can be formed or interconverted using ion exchange techniques.

A final aspect of the present invention relates to the use of the compounds of formula (I) for the treatment of premature labor, premature labor, painful menstruation, preferably the compounds of formula (I) are suitable for modulating the oxytocin receptor, the use of said compounds for producing pharmaceutical compositions for modulating the oxytocin receptor; also formulations containing the active compounds of formula (I). Said modulation of the oxytocin receptor is considered to be an appropriate approach to the treatment of preterm labor, preterm labor and painful menstruation. Therefore, pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient are also an object of the present invention. A person skilled in the art is familiar with a large number of such carriers, diluents or excipients suitable for the formulation of the pharmaceutical composition. The present invention also provides compounds for use as a medicament.

The compounds of the invention, together with commonly used adjuvants, carriers or excipients, may be present in the form of pharmaceutical compositions and unit doses thereof, and in this form may be used as solids such as tablets or filled capsules or liquids such as solutions, suspensions, emulsions, elixirs, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such dosage forms and unit dosage forms thereof may contain the components in conventional proportions with or without other active compounds or agents, and such dosage forms may contain any effective amount of the active ingredient in proportion to the daily dosage range employed.

When used as pharmaceuticals, the pyrrolidine derivatives of the invention are generally administered in the form of a pharmaceutical composition. These compositions can be prepared by a method known in the pharmaceutical art and comprise at least one active compound. In general, the compounds of the invention are administered in a pharmaceutically effective amount. The amount of compound administered is usually determined by the attending physician, having regard to the relevant circumstances,

• · · · ·

including the conditions of treatment, selecting the route of administration, the compound currently administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

The pharmaceutical compositions of the invention may be administered by various routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal administration. Oral compositions may be in the form of liquid solutions or suspensions or powders in bulk. However, more usually, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" means physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient, together with a suitable pharmaceutical excipient, producing the desired therapeutic effect. Typical unit dosage forms include pre-filled, pre-metered ampoules or syringes of liquid formulations or, in the case of solid formulations, pills, tablets, capsules or the like. In these compositions, the pyrrolidine oxadiazole compound is typically a minor component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight) and the remainder being various vehicles or carriers and process aids to form the desired dosage form.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles with buffers, suspending or dispersing agents, colorants, flavoring agents and the like. Solid forms may include, for example, any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or cellulose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavor.

• · ·

Injectable compounds are typically based on injectable sterile phosphate-buffered saline or saline or other injectable carriers known in the art. As mentioned above, the pyrrolidine derivatives of formula (I) are usually a minor component in these compositions ranging from 0.05 to 10% by weight and the remainder being the injectable carrier and the like.

The above compounds for oral administration or injectable compositions are merely representative. Other materials as well as process techniques and the like are set forth in Section 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, by the Marek Publishing Company, Easton, Pennsylvania, to which the present invention refers.

The compounds of the invention may also be administered in sustained release forms of the drug. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences, to which the present invention refers.

In the following, the invention will be illustrated by means of some examples, which, however, are not intended to limit the scope of the invention. The HPLC, NMR and MS data given in the Examples and below were obtained as follows. The following abbreviations are used in the examples: min (minute), hr (hour), g (gram), mmol (millimol), mp (melting point), eq (equivalents), mL (milliliter), pL (microliters), ACN (acetonitrile), Boc (butoxycarbonyl), CDCl ₃ (deuterated chloroform), CDI (carbonyldiimidazole), cHex (eyelohexaney), DCM (dichloromethane), DECP (diethylcyanophosphonate), DIC (diisopropyl carbodiimide), DMAP (4-dimethylaminopyridine) DMF dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d ₆ (deuterated dimethylsulfoxide), EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), EtOAc (ethyl acetate), Et ₂ O (diethyl ether), Fmoc (9 -fluorenylmethoxycarbonyl), HOBt (1-hydroxybenzotriazole), Kaiser oxime resin (4-nitrobenzophenone oxime resin); K ₂ CO ₃ (potassium carbonate), NaH (sodium hydride), NaHCO ₃ (sodium bicarbonate), nBuLi (n-butyllithium), TBTU (O-benzotriazolyl-A /, V, V ', Λ / tetramethyluronium) -tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid),

- 50 THF (tetrahydrofuran), TMOF (trimethyl orthoformate), MgSO ₄ (magnesium sulfate), PetEther (petroleum ether), rt (room temperature).

DETAILED DESCRIPTION OF THE INVENTION

Intermediate 1: (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (cf. Scheme 6, Compound XIII)

(2S, 4R) -1- (tert-butoxycarbonyl) -4-hydroxy-2-pyrrolidinecarboxylic acid (30g, 0.13mol) was dissolved in acetone (1500ml). A mechanical stirrer was placed in the flask and the solution was vigorously stirred. A freshly made 8N chromic acid solution was prepared by dissolving chromium trioxide (66.7g, 0.667mol) in water (40ml), adding concentrated sulfuric acid (53.3ml) and adding sufficient water to a solution volume of 115ml. A solution of 8N chromic acid (115ml) was then added dropwise over 30 minutes with vigorous stirring while maintaining the exothermic reaction at an optimum temperature of 25 ° C using an ice bath. After complete addition of chromic acid, the reaction mixture was stirred for an additional 15 minutes while maintaining an optimal temperature of 25 ° C. The reaction mixture was then quenched by the addition of methanol (20 mL). The exothermic reaction was controlled using an ice bath and if necessary by directly adding a small amount of crushed ice to the reaction mixture itself. The reaction mixture was then filtered through a pad of celite and then concentrated in vacuo. The resulting acid solution was then extracted with ethyl acetate (3 x 300 mL) and the combined organic layers were washed with brine (2 x 100 mL). The organic phase was then dried with magnesium sulfate and concentrated in vacuo. The crude product was recrystallized from ethyl acetate

formation of a white crystalline product, (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (22.55g, 76%). The antipode intermediate, (2R) 1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidine-carboxylic acid, was prepared according to the same protocol, starting from technical (2R, 4S) -1- (tert-butoxycarbonyl) -4- hydroxy-2-pyrrolidinecarboxylic acid.

1 H NMR (360MHz, CDCl 3); 1.4 (m, 9H); 2.5-3.0 (m, 2H); 3.7-3.9 (m. 2H); 4.75 (dd. 1H)

Intermediate 2: (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (cf. Scheme 4, Compound V)

A solution was prepared containing (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (intermediate 1, 5.0g, 21mmol) and O-methylhydroxylamine hydrochloride (2.7g, 32.8mmoi) in chloroform (100ml ), containing triethylamine (5.5g, 55mmol). The reaction mixture was stirred at ambient temperature overnight. And then the solvent was removed. The resulting crude reaction mixture was dissolved in ethyl acetate (150ml) and washed quickly with 1N HCl (40ml). The acidic layer was then extracted with ethyl acetate (3 x 20ml) and the combined organic layers were washed with brine and then dried over magnesium sulfate, filtered and then the solvent was removed in vacuo. The desired product (5.3g, 94%) was isolated as a pale yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ); 1.45 (m, 9H), 2.8-3.2 (m, 2H), 3.9 (s, 3H), 4.2 (m, 2H), 4.5-4.7 (m, 1H);

- 52 • 99 · · · 9 99 9 9

Intermediate 3: (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (ethoxvimino) -2-pyrrolidinecarboxylic acid (cf. Scheme 4, Compound V)

A solution was prepared containing (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (intermediate 1, 5.0g, 22mmol) and O-ethylhydroxylamine hydrochloride (6.4g, 65.5mmol) in a mixture of 1: 1 pyridine and ethanol (100ml). The reaction mixture was heated to reflux for 2.5 hours and then cooled and the solvent removed. The residue was dissolved in ethyl acetate and washed quickly with 1.3N HCl (40ml). The acidic layer was then extracted with ethyl acetate (3 x 20ml) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and then the solvent was removed in vacuo. The desired product (5.5g, 93%) was isolated as a pale yellow oil.

¹ H NMR (400 MHz, DMSO); 1.3 (t, 3H), 1.55 (m, 9H), 2.9-2.7 (m, 1 H), 3.4-3.1 (m, 1 H), 4.1-4.3 (m, 4 H), 4.6 (m, 1 H), 12- 13.5 (br. 1H).

Intermediate 4: (2S, 4EZ) -4- (allyloxy) imino-1- (tert-butoxycarbonyl) -2-pyrrolidinecarboxylic acid (cf. Scheme 4, Compound V)

A solution was prepared containing (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (intermediate 1, 5.0g, 22mmol) and O-allylhydroxylamine hydrochloride monohydrate (7.2g, 65.5mmol) in a mixture of 1 : 1 pyridine and ethanol (100ml). The reaction mixture was heated to reflux for 2.5 hours and then cooled and the solvent removed. The residue was dissolved in ethyl acetate and washed quickly with 1.3N HCl (40ml). The acidic layer was then extracted with ethyl acetate (3 x 20ml) and the combined organic layers were washed with brine and then dried over magnesium sulfate, filtered and then the solvent was removed in vacuo. The desired product (5.9g, 94%) was isolated as a pale yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ); 1.5 (m, 9H), 2.8-3.2 (m, 2H), 4.2 (m, 2H), 4.5-4.7 (m, 3H), 5.25 (m, 2H), 5.9 (m, 1H), 11.1 (broad S) , 1H).

Intermediate 5: (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- {f (4-methoxybenzyl) oxyjimino} -2-pyrrolidinecarboxylic acid (cf. Scheme 4, Compound V)

Using the same procedure used in the preparation of intermediate 2, starting from (2S) -1- (tert-butoxycarbonyl) -4-oxo-2-pyrrolidinecarboxylic acid (intermediate 1) and 1 - [(aminooxy) methyl] -4 -methoxybenzene (intermediate 6) gave the title compound as a gum in 85% yield.

Ή NMR (400 MHz, DMSO); 1.5 (m, 9H), 2.7-2.9 (m, 1H), 3.9 (s, 3H), 4.2 (m, 3H), 4.6 (m, 1H), 5.15 (s, 2H), 7.1 (d, 2H), 7.45 (d. 2H).

Intermediate 6: 1-f (Aminooxy) methyl] -4-methoxybenzene (cf. Scheme 5, Compound X)

- 55 • ·

A solution of N-Boc-hydroxylamine (2.0g, 17.1mmol) in dry THF (60ml) was made. Sodium hydride (1.1g of a 60% suspension in paraffin oil, 25.7mmol) was then added and the suspension was stirred. A catalytic amount of KJ was then added to the reaction mixture prior to the careful addition of 4-methoxybenzyl chloride (3.2g, 20.4mmol). The reaction mixture was stirred overnight and then the solvent was removed in vacuo. The residue was taken up in diethyl ether (100 mL) and HCl gas was bubbled through for 20 minutes, causing the product to precipitate. The flask was closed with a stopper and left overnight. The product was filtered as off-white wax (39-52% yield according to different designs).

¹ H NMR (400 MHz, D ₂ O): 3.8 (s, 3H), δ (s, 2H), 7.0 (d, 2H), 7.4 (d, 2H).

Intermediate 7: Non-technical amidoxime

Method A. for example N-hydroxyethanimidamide (acetamidoxime) (cf. Scheme 2, Compound VI)

To 90 ml of a 50% hydroxylamine / 50% water (w / w) mixture was added 45 ml of high purity acetonitrile and the mixture was stirred with a magnetic stirrer at 25 ° C. Mostly crystalline N-hydroxyethanimidamide separated. The mixture was stirred at room temperature for 24 hours, whereupon crystals were completely formed, and filtered the next day. In cases where no solids were initially separated, a small amount of solution was collected, evaporated and the formed crystals were used to inoculate a large amount of solution. The product was purified as follows: the crystals were filtered and then dissolved in a nonpolar solvent (perfluorohexane) with heating and the solution was cooled to room temperature overnight for recrystallization. The crystalline material was then filtered and washed with perfluorohexane. The desired product, N-hydroxyethanimidamide, had a melting point of 136 ° C-138 ° C and a yield of about 56%.

•

Method B: e.g. tert-Butyl-2-amino-2- (hydroxyimino) ethylcarbamate (Scheme 2, Compound XI)

Triethylamine (535μΙ, 3.84mmol) was added to a solution of tert-butyl cyanomethylcarbamate (500mg, 3.20mmol) and hydroxylamine hydrochloride (227mg,

3.84 mmol) in ethanol (10 mL). The reaction mixture was then heated at 80 ° C overnight. The resulting solution was then evaporated in vacuo. Ethyl acetate (10ml) was added to the residue and the triethylamine hydrochloride was removed by filtration. The solution was then evaporated in vacuo to give the crude product.

¹ H NMR (360 MHz, DMSO); 1.53 (s, 9H); 3.62-3.63 (d, 2H); 5.33-5.44 (s, 2H); 7.10 (t, 1H); 8.94 (s, 1H).

Similarly, using Method B and the appropriate starting carbonitriles and hydroxylamine hydrochloride, the following amidoxime intermediates were obtained: (2RS) -N, 2-dihydroxybutanimidamide, (1S, 2R) - (1 ', 2-dihydroxycyclohexanecarboximidamide); N ', 3-dihydroxypropanimidamide, N', 2-dihydroxyethanimidamide, (2 S) - N ', 2-dihydroxy-2-phenylethanimidamide, tert-butyl 4- [amino (hydroxyimino) methyl] -1 -piperidinecarboxylate, tert-butyl (3RS) -3- [amino (hydroxyimino) methyl] -1-piperidinecarboxylate, tert-butyl (2RS) -2- [amino (hydroxyimino) methyl] -1-piperidinecarboxylate, ethyl amino (hydroxyimino) ethanoate .

- 56 Intermediate 8: (2S, 4EZ) -1- (1,1'-biphenyl-4-ylcarbonyl) -N-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (Scheme 8, Compound XV)

In a 3 liter flanged flask was charged 1- (tert-butoxycarbonyl) -4 (methoxyimino) -2-pyrrolidinecarboxylic acid (Intermediate 2, 95.9g, 0.371mol), equipped with a stirrer, nitrogen inlet / outlet and temperature probe from above. Dry THF (1.15L) was then added to the flask and the solution was cooled to -20 ° C before the addition of triethylamine (52mL, 0.371mol). The solution was then stirred for 10 minutes. Ethyl chloroformate (35ml, 0.371mol) was added to the solution for 10 minutes while maintaining the temperature around -20 ° C. The reaction mixture was then stirred for an additional 30 minutes at this temperature. A solution of ammonia saturated THF was made by bubbling ammonia through 250 mL of dry THF for 15 minutes at -78 ° C. The ammonia solution was added to the reaction flask via cannula for 10 minutes while maintaining the reaction temperature below -25 ° C to control the exothermic reaction. The solution was allowed to stand for 2 hours to reach room temperature and then stirred for an additional hour. The solvent was removed from the reaction mixture in vacuo and the residue was partitioned between dichloromethane (500mL) and water (500mL). After separation, the organic layer was washed with 3 x 250mL of water, the combined aqueous layers were then washed with 2 x 250mL of DCM, and this DCM was backwashed with 100mL of water. The combined organic layers were then dried over sodium sulfate, filtered and the solvent removed in vacuo. The desired product, tert-butyl (2S, 4EZ) -2- (aminocarbonyl) -4- (methoxyimino) -1-pyrrolidine-carboxylate, was obtained as a white amorphous solid (85.8g, 90%).

¹ H NMR (400 MHz, DMSO); 1.5 (s, 9H), 2.65 (m, 1 H), 3.15 (m, 1 H), 3.9 (s,

3H), 4.2 (m, 2H), 4.5 (m, 1 H), 7.2 (m, 1 H), 7.65 (m, 1 H).

57 In a 1L round bottom flask was charged tert-butyl (2S, 4EZ) -2- (aminocarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylate (20g, 77.7mmol) under an inert atmosphere. Then dry dichloromethane (140mL) was added to the flask followed by TFA (60mL). The reaction mixture was stirred at room temperature for 90 minutes while monitoring the loss of starting material by tle (10% MeOH in DCM). Toluene (200mL) was then added to the reaction mixture and the solvents were removed in vacuo. The residue was redissolved in DCM (200mL), cooled to -5 ° C and triethylamine (43mL, 311mmol) was added (exothermic reaction). [1,1'-Biphenyl] -4-carbonyl chloride (16.8g, 77.7mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. At this point, additional DCM (500mL) and 1M HCl (250mL) were added. The mixture was stirred vigorously and the precipitate was filtered. The filtrate layers were separated, the organic layer was washed with 1M HCl (250mL) and saturated bicarbonate (250mL). The basic aqueous layer was back washed with DCM (250mL), and the combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated to a volume of ca. 200mL. The resulting slurry was filtered to give the desired product, (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxamide as an off-white solid (7.3g). , 28%). An additional amount of less pure material (7.9g, 30%) could be obtained by adding hexane (125mL) to the filtrate.

¹ H NMR (400 MHz, DMSO); 2.6 (m, 1 H), 3.2 (m, 1 H), 3.8 (m, 3 H), 4.1-4.5 (m, 2 H), 4.9 (m, 1 H), 7.2-8.0 (m, 1 H).

In a round bottom flask was added (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4 (methoxyimino) -2-pyrrolidinecarboxamide (7.46g, 22.1 mmol), pyridine (400mL) and p-toluenesulfonyl chloride (4.21g, 22.1mmol) was added. The resulting suspension was heated at 80 ° C for 4 hours. The solvent was removed in vacuo and the residue was dissolved in DCM (400mL), the solution was washed with 1M HCl (2 x 75mL) saturated bicarbonate (70mL) prior to drying over sodium sulfate, filtered and the solvent removed in vacuo. Purification by silica gel chromatography, eluting initially with dichloromethane to remove the less polar material, followed by 1% MEOH in DCM gave the desired product.

- 58 · · 58 58 58 58 58 58 58 58 58

B · · · ··· <

• «· · í>

compound, (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) -2-pyrrolidinecarbonitrile, as an off-white solid (4.2g, 60%).

¹ H NMR (400 MHz, DMSO); 3.0 (m, IH), 3.2 (m, IH), 3.7 (m, IH), 4.2 (m, IH), 4.5 (m, IH), 5.4 (m, IH), 7.4-7.8 (m, IH) .

According to the above general process for the synthesis of intermediates 8, a suspension of (2S, 4EZ) -1 - ([1, T-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) -2-pyrrolidinecarbonitrile (3.71g, 11.62mmol) and hydroxylamine hydrochloride (0.97g, 13.94mmol) in ethanol (150ml) was slowly added triethylamine (1.94ml, 13.94mmol) under stirring. The reaction mixture was then stirred slowly at 80 ° C for 16 hours and then cooled to ambient temperature. The solvent was removed by evaporation and the solid was suspended in water (100ml) and then filtered. The solid was washed with diethyl ether (2 x 100ml) and then dried in vacuo at 40 ° C to give the desired product, (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N -hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (3.35g, 82%).

¹ H-NMR (400MHz, DMSO): 2.6-2.7 (m, 1 H), 2.9-3.1 (m, 1 H), 3.6-3.75 (m, 3 H), 4.0-4.2 (m, 1 H), 4.2-4.4 ( m, 1H), 4.6 (m, 0.5H), 5.1 (m, 0.5H), 5.5 (m, 2H), 7.4-7.8 (m, 9H), 9.2-9.4 (m, 1H).

Intermediate 9: tert-butyl (2S, 4EZ) -2- (hydrazinocarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylate (Scheme 10, Compound XVII)

A solution was prepared containing, for example, (4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2, 17.81 mmol; 4.6g) in a 1: 1 mixture of methanol and toluene (250mL). Then do

Trimethylsilyl diazomethane (32.5mL 2M solution in hexanes, 59mmol) was added dropwise at room temperature under nitrogen at room temperature. After complete evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo and the residue redissolved in DCM and washed with saturated NH ₄ Cl and 10% NaHCO ₃ , and brine, dried over Na ₂ SO ₄ and evaporated in vacuo to give the title compound, 1-tert-butyl 2-methyl (2S, 4ZZ) -4- (methoxyimino) -1,2-pyrrolidine dicarboxylate as a yellow oil (4.0g, 83%).

1-tert-Butyl 2-methyl (2S, 4EZ) -4- (methoxyimino) 1,2-pyrrolidinedicarboxylate (1.95 mmol; 530mg) was dissolved in 4mL MeOH and a solution of 4mL MeOH and 1.5mL (d = 1.03) was added. 30.86 mmol) 80% hydrazine hydrate (final c (NH ₂ NH ₂ ) = 13%). The reaction mixture was stirred for 2 days. The solvents were evaporated in vacuo and the residue was redissolved in MeOH and evaporated (3x). The desired product, tert-butyl (2S, 4Ez) -2- (hydrazinocarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylate, was isolated as a yellow oil (500mg; 94%).

¹ H-NMR (CDCl ₃ ): 1.47 (s, 9H, CH 3), 2.8-3.2 (m, 2H, CH 2), 3.87 (s, 3H, CH 3 O), 3.95-4.3 (m, 2H, CH 2), 4.52 (m, 1 H, CH-N). MS (APCI ⁺ ): 273.0, 545.4 (2M, ⁺¹ ).

Intermediate 10: 2'-Methyl-N-biphenyl-N-carboxylic acid

To a mixture of 4-bromobenzoic acid (30g, 0.15mol), 2-methylphenylboronic acid (24g, 0.15 mol), sodium carbonate (250g) in toluene (500mL) and water (500mL) was added tetrakis-triphenylphosphine palladium (O) under nitrogen. (9g, 0.0074mol). The reaction mixture was refluxed for 10 hours. After this time, 100 mL of 10% NaOH was added to the reaction mixture, the aqueous layer was separated and washed with toluene (2x200mL). Acidification of the aqueous layer with 3N HCl gave the product as a solid, which was filtered, washed with water and dried. The crude product was then crystallized from toluene to give

60 2'-methyl [1,1'-biphenyl] -4-carboxylic acid (20g, 62.5%).

Conversely, the product could also be obtained from 1-bromo-2-methylbenzene and 4-carboxybenzeneboronic acid using analogous conditions.

¹ H NMR (300 MHz, DMSO); 2.2 (s, 3H), 7.2-7.4 (m, 4H), 7.43 (d, J = 9 Hz, 2H), 7.99 (d, J = 9 Hz, 2H), 13 (b, 1H).

Similarly, using the appropriate industrial boronic acids and aryl bromides, the following 1,1'-biphenyl derivatives were obtained, related to intermediate (12): 4'methyl [1,1'-biphenyl] -4-carboxylic acid; 2 ', 3-dimethyl [1,1'-biphenyl] -4-carboxylic acid; 2 ', 6'-dimethyl [1,1'-biphenyl] -4-carboxylic acid; 2-methyl- [1,1'-bienyl] -4-carboxylic acid; 3-methyl- [1,1'-biphenyl] -4-carboxylic acid; 2,2'-dimethyl [1,1'-biphenyl] -4-carboxylic acid; 2'-methoxy- [1,1'benyl] -4-carboxylic acid; 3'-methoxy [1,1'-biphenyl] -4-carboxylic acid; 4'-methoxy [1,1'-biphenyl] -4-carboxylic acid; 2'-chloro [1,1'-biphenyl] -4-carboxylic acid; 3'-chloro [1,1'-biphenyl] -4-carboxylic acid; 4'-chloro [1,1'-biphenyl] -4-carboxylic acid; 3 ', 4'-dichloro [1,1'-biphenyl] -4-carboxylic acid; 2 '- (trifluoromethyl) [1,1'-biphenyl] -4-carboxylic acid; 3 '- (trifluoromethyl) [1,1'-biphenyl] -4-carboxylic acid; 2'-cyano [1,1'-biphenyl] 4-carboxylic acid; 2 ', 4'-difluoro [1,1'-biphenyl] -4-carboxylic acid; 4- (2-pyridinyl) benzoic acid; 4- (3-pyridinyl) benzoic acid; 4- (4-pyridinyl) benzoic acid; 4- (5-pyrimidinyl) benzoic acid; and other.

Intermediate 11: 4- (3-Methyl-2-pyridinyl) benzoic acid

A mixture of 2-bromo-3-methylpyridine (22.5g, 0.1312mol), 4- (hydroxymethyl) phenylboronic acid (25g, 0.164mol), Pd (PPh ₃ ) 4 (9.5g, 0.0082mol) and sodium carbonate (200g in 500 ml of water) in toluene (750 ml) was refluxed under a nitrogen atmosphere for 15 hours. Separation of the toluene layer and distillation under reduced pressure gave a residue. The residue was then purified by column chromatography to give [4- (3-methyl-2-pyridinyl) phenyl] methanol (12g, 47%).

To a solution of [4- (3-methyl-2-pyridinyl) phenyl] methanol (12g, 0.06mol) dry DMF (150mL) was added pyridinium dichloride (91g, 0.24mol) the mixture was stirred.

at room temperature 3dny. The reaction mixture was poured into water and extracted with ethyl acetate (250mL). The organic layer was washed with water, brine, dried and concentrated. The crude product was purified by silica gel column chromatography to give 4- (3-methyl-2-pyridinyl) benzoic acid (3g, 25%) as a white solid.

¹ H NMR (300 MHz, DMSO); 2.3 (s, 3H), 7.33 (dd, J = 7.5 Hz, 5Hz, 1H), 7.67 (d, J = 8 Hz, 2H), 7.75 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 8Hz, 2H), 8.50 (d, J = 5Hz, 1 H), 13 (b, 1 H).

Intermediate 12: 4- (1-Qxido-3-pyridinyl) benzoic acid

To a mixture of 4-tolylboronic acid (38g, 0.28mol), 3-bromopyridine (44g, 0.28mol), Na ₂ CO ₃ (200g) in toluene (500ml) and water (500ml) was added Pd (PPh ₃ ) 4 (16g) , 0.014mol), and the mixture was refluxed for 16 hours. The reaction mixture was cooled and the separated organic layer was washed with water and brine and dried. The solvent was removed to give 4- (3-pyridyl) toluene (42g, 90%).

To a mixture of 4- (3-pyridyl) toluene (35g, 0.207mol) in pyridine (400ml) and water (400ml) was added KMnO ₄ (163g, 1.03mol) in portions and the mixture was refluxed for 12 hours. The reaction mixture was filtered through a pad of celite and acidified with conc. HCl. The product was washed with water and dried to give 4- (3-pyridyl) benzoic acid (32g, 76%) as a white solid. To a mixture of 4- (3-pyridyl) benzoic acid (22g, 0.11mol) in THF (2.5I) was added mCPBA (152g, 0.44mol, 50%) and the mixture was stirred at room temperature for 12 hours. The solid was filtered and washed with THF to give 4- (1-oxido-3-pyridinyl) benzoic acid (20g, 86%).

¹ H NMR (300 MHz, DMSO); 7.5-7.8 (m, 5 H), 7.9 (d, J = 8 Hz, 2H), 8.33 (d, J = 5 Hz, 2H).

Similarly, 4- (1-oxido-2-pyridinyl) benzoic acid was obtained from 4-tolylboronic acid (45g, 0.33mol) and 2-bromopyridine (52g, 0.33mol).

• ·

Example 1:

General method for the synthesis of the dissolved phase of pyrrolidine oxadiazole derivatives of the general formula I, wherein B = Ha (schemes 1.11): (3EZ, 5S) -1- (1,1,1'-biphenyl-4-ylcarbonyl) -5- (3-methyl-1) 2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime;

(3E, 5S) -1-r (2'-Methyl- [1,1'-biphen-4-yl) carbonyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O - (3Z, 5S) -1 - [(2'-methyl-1,1'-biphenyl-4-yl) carbonyn-5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime.

a) Protocol for oxadiazole ring formation

Diisopropylcarbodiimide (3.16g, 25.17mmol) was added to a solution of (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2, 6.50g, 25.17mmol) and acetamidoxime ( intermediate 7, 1.86g, 25.17mmol) in DCM (55ml) and the mixture was stirred overnight at room temperature (DCM-insoluble amidoximes were pre-dissolved in THF to which a solution of DIC and intermediate 2 in DCM was added). After pump filtration and evaporation in vacuo, the residue was dissolved in pyridine (60ml) and the solution was refluxed for one hour, then cooled and allowed to stand overnight, then evaporated in vacuo. The crude product was then dissolved in DCM (50ml) and washed with saturated NaHCO ₃ (aq) (2 x 50ml) followed by 1M HCl (aq) (2 x

• · · ·

50 ml), dried over magnesium sulfate and evaporated in vacuo (crude yield 70%). Silica gel chromatography, eluting with 15% ethyl acetate in hexanes, gave the title compound, tert-butyl (2S, 4EZ) -4- (methoxyimino) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -1-pyrrolidinecarboxylate (4.4). g, 60% yield).

¹ H NMR (360 MHz, DMSO); 1.3-1.6 (d, 9H), 2.4 (s, 3H), 2.8-3.4 (m, 2H), 3.9 (s, 3H), 4.3 (s, 2H), 5.2-5.4 (m, 1H).

b) Protocol for the N-protecting group removal step

A solution was prepared containing tert-butyl (2S, 4ZZ) -4- (methoxyimino) -2- (3-methyl-1,2,4-oxadiazol-5-yl) -1-pyrrolidinecarboxylate (1.26 g, 4.25 mmol) in anhydrous DCM (120 mL). At 0 ° C, HCl gas, which had previously been dried with a H ₂ SO ₄ cc separator, was slowly bubbled through the reaction mixture and the deprotection was monitored by TLC using cyclohexane / ethyl acetate (1/1) and stained with pancaldi solution. After about 45 minutes, TLC showed no starting material and the DMC was then evaporated in vacuo without heating to prevent decomposition of the pyrrolidine salt. Then more DCM (20 mL) was added and the solution was evaporated again to remove the remaining HCl potential (2-3 times). The desired product, (3R, 5S) -5- (3-methyl-1,2,4oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime hydrochloride salt, was isolated as a white solid and used without further purification and characterization.

c) Protocols for the N-closure step

Method A: To a solution of (3EZ, 5S) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime hydrochloride salt (200mg, 0.86mmol) in DCM (5ml) was added [1,1'-Biphenyl] -4-carbonyl chloride (205mg, 0.95mmol) followed by diisopropylethylamine (314µl, 1.81mmol) and the mixture was stirred overnight at room temperature. Aminomethyl-polystyrene resin (250mg) was added to the reaction mixture and the mixture was stirred for one hour before filtering with a pump. The solution was washed with citric acid (aqueous) (2 x 5ml) and then dried over MgSO ₄ , and evaporated in vacuo. Product, (3R, 5S) -1 - ([1,1'-Biphenyl] -4ylcarbonyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime, se

purified by silica gel chromatography, eluting with 20% ethyl acetate in hexanes (60mg, 19% yield)

Method B: A solution was prepared containing (3EZ, 5S) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime hydrochloride salt, 2'-methyl [1,1biphenyl] -4-carboxylic acid (0.857g, 4.04 mmol, 0.95 eq) and optionally DMAP (1.03 g, 8.50 mmol, 2.0 eq) in dry DCM (120 mL). The reaction mixture was stirred at RT for 10 minutes and then cooled to 0 ° C. EDC, HCl (815 mg, 4.25 mmol) was slowly added portionwise at 0 ° C over 30 min. The reaction mixture was stirred at 0 ° C for 2 hours and slowly warmed to RT overnight. Once the reaction was complete, the organic phase was washed twice with citric acid (10%) and sodium carbonate (10%). The organic phase was dried and evaporated. The crude product was purified and separated into (E) and (Z) -isomers by column chromatography (Biotage system, 40M column, 90 g SiO ₂ , using cyclohexane / ethyl acetate (1/1) as eluent) to afford (3E, 5S ) -1 - [(2'-Methyl [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (770 mg, 34%) (colorless oil, 97.5% purity by HPLC) and (3Z, 5S) -1 - [(2'-methyl [1,1'-biphenyl] -4-yl) carbonyl] -5- ( 3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (740 mg, 33%) (colorless oil, 98.3% HPLC purity).

(3E, 5S) -1 - [(2'-Methyl [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3- pyrrolidinone O-methyloxime: oil; ¹ H NMR (300 MHz, CDCl ₃ ): 2.28 (s, 3H, ArCH ₃ ), 2.42 (s, 3H, CH ₃ ), 3.03-3.32 (m, 2H), 3.88 (s, 3H, NOCH ₃ ), 4.384.59 (m, 2H), 6.03 (m, 1H), 7.22-7.29 (m, 5H, aromatic H), 7.40-7.44 (m, 2H, aromatic H), 7.55 (m, 1H); MS (APCI &lt; ⁺ &gt;):391.5; MS (APCL) 389.2.

(3Z, 5S) -1 - [(2'-Methyl [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime: white solid, mp 146.5 ° C; IR (neat) at 2936, 1645, 1583, 1408, 1323, 1047, 890 cm ^-1 ; ¹ H NMR (300 MHz, CDCl _3): 2.28 (s, 3H, Ar / 7 _3), 2.42 (s, 3H, _CH3), 3.03 to 3.32 (m, 2H), 3.88 (s, 3H, NOCH ₃ ), 4.38-4.59 (m, 2H), 6.03 (m, 1H), 7.22-7.29 (m, 5H, aromatic H), 7.407.44 (m, 2H, aromatic H), 7.55 (m, 1H) ; MS (APCI &lt; ⁺ &gt;):391.5; MS (APCI) 389.2

- 65 * · ···· · · · · · · · · · · · · ·

Example 2:

(3 EZ, 5 S) -1 - _[(2'-1 chloroí1 bifenvl1-4 1'-yl) karbonyn-5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime ?

According to the general methods outlined in Example 1 (Method B), (2S, 4EZ) -1- (tert -butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), N-hydroxyethanimidamide (intermediate) 7) and 2'-chloro [1,1-biphenyl] -4-carboxylic acid (intermediate 10) after flash chromatography isolates the title compound as a mixture of the E / Z isomers as an oil in 31% yield (98.5% HPLC purity).

Oil; ¹ H NMR (300 MHz, CDCl ₃ ): 2.41 (s, 3H, CH ₃ ), 2.96-3.31 (m, 2H, CH ₂ ),

3.87 (s, 3H, NOCH), 4.31 to 4.59 (m, 2H, _CH2), 6.03 (m, 1H), 7.30 (s, 3H, H arom.), 7.50 to 7.64 (m, 5H, arom. H ); MS (ESI &lt; ^{+ &} gt ^; ): 411.2; MS (ESL) 408.9.

Example 3:

(3EZ, 5S) -5- (3-Methyl-1,2,4-oxadiazol-5-yl) -1- {2 '- (trifluoromethyl) -1,1'-biphenyl-4-ylcarbonyl} -3-pyrrolidinone O- methvloxim \

?

According to the general methods outlined in Example 1 (Method B), (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2),, / - hydroxyethanimidamide (interm. 7) and 2 '- (trifluoromethyl) [1,1'-biphenyl] -4-carboxylic acid (interm. 10) after flash chromatography isolates the title compound as a mixture of E- / Z-isomers as an oil in 44% yield. (88.2% HPLC purity).

Oil; ¹ H NMR (300 MHz, CDCl ₃ ): 2.40 (s, 3H, CH ₃ ), 2.88-3.31 (m, 2H, CH ₂ ),

3.87 (s, 3H, NOCH _3), 4.27 to 4.53 (m, 2H, _CH2), 6.03 (m, 1H), 7.27 to 7.70 (m, 7H, arom. H), 7.77 (m, 1H, arom H .); MS (ESI &lt; ^{+ &} gt ^; ): 445.4; MS (ESI) 443.1.

Example 4:

(3E, 5S) -1-f (2'-fluoro [1,1'-biphenyl-4-yl) carbonyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O -methyloxime and (3Z, 5S) -1 - [(2'-fluoro [1,1'-biphenyl-4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3 -pyrrolidinone O-methyloxime

According to the general methods outlined in Example 1 (Method B), (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), N-hydroxyethanimidamide ( Intermediate 7) and 2'-fluoro [1,1'-biphenyl] -4-carboxylic acid (Intermediate 10) gave the title compounds as a mixture of E- / Z-isomers and were then separated by flash chromatography to afford (3E, 5S) -1. - [(2'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5yl) -3-pyrrolidinone O-methyloxime in 11% yield (95.0% purity by HPLC) and (3Z, 5S) -1 - [(2'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4- oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime in 11% yield (98.2% purity by HPLC).

67 (3E, 5S) -1 - [(2'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) - 3-pyrrolidinone O-methyloxime: oil; ¹ H NMR (300 MHz, CDCl _3): 2.42 (s, 3H, _CH3), 3.07 to 3.25 (m, 2H, _CH2), 3.87 (s, 3H, NOC / 7 _3), 4.42 to 4.52 (m , 2H, CH _2), 6.04 (m, 1H), 7.15 to 7.29 (m, 2H, H arom.), 7.30 to 7.44 (m, 2H, H arom.), 7.70 (m, 4H); MS (ESI &lt; ^{+ &} gt ^; ): 395.0; MS (ESI +): 393.0.

(3Z, 5S) -1 - [(2'-Fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3 -pyrrolidinone O-methyloxime: oil; ¹ H NMR (300 MHz, CDCl ₃ ): 2.42 (s, 3H, CH ₃ ), 3.02 (m, 1H, CH), 3.25 (m, 1H, CH), 3.87 (s, 3H, NOCH ₃ ), 4.34 -4.58 (m, 2H, _CH2), 6.04 (m, 1H), 7.15 to 7.29 (m, 2H, H arom.), 7.30 to 7.44 (m, 2H, H arom.), 7.70 (m, 4H) ; MS (EST) 395.0; MS (ESI +): 393.0.

Example 5:

(3 EZ, 5 S) -1-f (4'-fluoro [1 _l bifenyl1-4-1'-yl) karbonvl1-5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O -methyloxim

According to the general methods outlined in Example 1 (Method B), (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), N-hydroxyethanimidamide ( Intermediate 7) and 4'-fluoro [1,1-biphenyl] -4-carboxylic acid (Intermediate 10) after flash chromatography isolated the title compound as a mixture of E / Z isomers as an oil in 32% yield (94.1% HPLC purity). .

Oil; 1 H NMR (300 MHz, CDCl ₃ ): 2.42 (s, 3H, CH ₃ ), 2.95-3.30 (m, 2H, CH ₂ ),

3.87 (s, 3H, NOCH _3), 4.27 to 4.55 (m, 2H, _CH2), 6.02 (m, 1H), 7.12 (m, 2H, H arom.), 7.27 to 7.61 (m, 6H, H arom .); MS (ESI &lt; ^{+ &} gt ^; ): 395.5; MS (ESI - 393.4).

- 68 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 6:

(3EZ, 5S) -1- (2'-chloro-4'-fluoro-1,1'-biphenyl-4-carbonyl) -5- (3-methyl-1,2,4oxadiazol-S-yl) -5-pyrrolidinone O -methyloxime (3Z, 5S) -1 - _{[(2'-chloro-4'-1'-L} fluoroÍ1 bifenvH-4-yl) karbonvl1-5- (3-methyl-1,2,4-oxadiazol-5 -vl) -3-pyrrolidinone methylmethyloxime

According to the general methods outlined in Example 1 (Method B), (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), N-hydroxyethanimidamide ( Intermediate 7) and 2'-chloro-4'fluoro [1,1'-biphenyl] -4-carboxylic acid (Intermediate 10) after flash chromatography isolates the title compound as a mixture of E / Z isomers as an oil in 60% total yield (95.20% HPLC purity). Subsequent flash chromatography gave (3Z, 5S) -1 - [(2'-chloro-4'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2) 4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime in 30% yield (97.5% purity by HPLC).

(3EZ, 5S) -1 - [(2'-Chloro-4'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazole-5- yl) -3-pyrrolidinone O-methyloxime: oil; ¹ H NMR (300 MHz, CDCl ₃ ):

2.31 (s, 3H, _CH3), 2.78 to 3.24 (m, 2H, _CH2), 3.77 (s, 3H, NOCH _3), 4.30 to 4.52 (m, 2H, _CH2), 5.93 (m, 1H) 6.88-7.60 (m, 7H, aromatic H); MS (ESI ⁺ ), 429.20.

(3Z, 5S) -1 - [(2'-chloro-4'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazole-5- yl) -3-pyrrolidinone O-methyloxime: oil; ¹ H NMR (300 MHz, CDCl ₃ ):

2.31 (s, 3H, _CH3), 2.78 to 3.24 (m, 2H, _CH2), 3.77 (s, 3H, NOCH _3), 4.30 to 4.52 (m, 2H, _CH2), 5.93 (m, 1H) 6.88-7.60 (m, 7H, aromatic H); MS (ESI ⁺ ), 429.20.

Example 7:

(3EZ, 5S) -1- (2 ', 4'-Difluoro-1H-biphenyl-4-ylcarbonyl) -1-SO-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime; (3Z, 5S) -1 - [(2 ' ₁ 4'-Difluoro-1,1'-biphenyl-4-yl) -carbonyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) - 3-pyrrolidinone O-methyloxime; (3E, 5S) -1-r (2 ', ^4' -difluorof1, U-biphenyl--yDkarbonyll-SO-methyl-L-Aoxadiazol-S-S-YD-pyrrolidinone O-methyloxime.

According to the general methods outlined in Example 1 (Method B), from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), N-hydroxyethanimidamide ( Intermediate 7) and 2 ', 4'-difluoro [1,1'-biphenyl] -4-carboxylic acid (Intermediate 10) after flash chromatography isolates the title compound as a mixture of E- / Z-isomers as an oil in 37% overall yield. (98.6% HPLC purity). Subsequent resolution of the E- and Zisomers by flash chromatography gave (3Z, 5S) -1 - [(2 ', 4'-difluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl- 1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime in 15% yield (98.5% HPLC purity), and (3E, 5S) -1 - [(2 ', 4'd if fluorine [1]) 1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime in 13% yield (97.5% purity) HPLC).

(3EZ, 5S) -1 - [(2 ', 4'-Difluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) ) -3-pyrrolidinone O-methyloxime: oil; ¹ H NMR (300 MHz, CDCl ₃ ):

2.34 (s, 3H, _CH3), 2.86 to 3.25 (m, 2H, _CH2), 3.79 (s, 3H, NOCH _3), 4.30 to 4.52 (m,

2H, _CH2), 5.96 (m, 1H), 6.82 to 7.01 (m, 2H, Harom), 7.32 to 7.66 (m, 5H, arom H); MS (ESI ⁺ ), 413.40; MS (ESI) 411.20.

-70 (3Z, 5S) -1 - [(2 ', 4'-difluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazole- 5-yl) -3-pyrrolidinone O-methyloxime: oil; ¹ H NMR (300 MHz, CDCl 3):

2.31 (s, 3H, _CH3), 2.78 to 3.24 (m, 2H, _CH2), 3.77 (s, 3H, NOCH _3), 4.30 to 4.52 (m, 2H, _CH2), 5.93 (m, 1H) 6.88-7.60 (m, 7H, aromatic H); MS (ESI ⁺ ), 413.40; MS (ESI) 411.20.

(3E, 5S) -1 - [(2 ', 4'-Difluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazole) -5-yl) -3-pyrrolidinone O-methyloxime: oil; ¹ H NMR (300 MHz, CDCl ₃ ):

2.31 (s, 3H, _CH3), 2.78 to 3.24 (m, 2H, _CH2), 3.77 (s, 3H, NOCH _3), 4.30 to 4.52 (m, 2H, _CH2), 5.93 (m, 1H) 6.88-7.60 (m, 7H, aromatic H); MS (ESI ⁺ ), 413.40; MS (ESI) 411.20.

Example 8:

(3EZ, 5S) -1- (4'-fluoro-2'-methyl [1,1'-biphen-4-yl) carbonyl-5- (3-methyl-1,2,4oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime.

According to the general methods outlined in Example 1 (Method B), (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), N-hydroxyethanimidamide ( Intermediate 7) and 4'-fluoro-2'methyl [1,1'-biphenyl] -4-carboxylic acid (Intermediate 10) after flash chromatography isolated the title compound as a mixture of E- / Z-isomers as an oil in 14% total yield (95.2% HPLC purity).

Oil; ¹ H NMR (300 MHz, CDCl ₃ ): 2.17 (s, 3H, CH ₃ ), 2.34 (s, 3H, CH ₃ ), 2.863.26 (m, 2H, CH ₂ ), 3.80 (s, 3H, NOCW) ₃₎ 4.33 to 4.45 (m, 2H, _CH2), 5.97 (m, 1H), 6.82 to 6.95 (m, 2H, Harom), 7.10 to 7.66 (m, 5H, arom H); MS (ESI &lt; ^{+ &} gt ^; ): 409.33; MS (ESI) 407.11.

- 71 Example 9:

(3E, 5S) -1 - ((1,1'-Biphenyl-4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl) -3-pyrrolidinone Q-methyloxime (3Z, 5S) -1 - ([1,1'-Biphenyl-4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazole-5-yl] -3-pyrrolidinone Q-methyloxime .

According to the general methods outlined in Example 1 (Method B), (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), N, 3-dihydroxypropanimidamide ( Intermediate 7) and [1,1'-Biphenyl] -4-carboxylic acid (Intermediate 10) after flash chromatography isolated the title compound as a mixture of E- / Z-isomers as an oil in 64% overall yield (90% HPLC purity). At this stage, a purification was performed by flushing with pol-trisamine in DCM (Novabiochem) to remove excess acid by-products that fell out and would be difficult to remove by a flash chromatography column. The E- and Z-isomers were finally resolved by flash column chromatography (Biotage system, 40M column, 90 g SiO ₂ , using cyclohexane / ethyl acetate (2/8) as eluent to give (3E, 5S) -1 - ([ 1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime in 25% yield (98.0% purity by HPLC and (3Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime in 25% yield (99.5% purity by HPLC).

(3E, 5S) -1 - ([1,1'-Biphenyl] -4-ylarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O- methyloxime: white solid, mp 140.5 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): 2.98-3.05 (m, 3H, CW ₂ ), 3.33 (m, 1H, CH ₂ ), 3.86 (s, 3H, OCH ₃ ), 4.35-4.57 (m, 2H) CH ₂ ), 6.04 (m, 1 H, CH), 7.38-7.51 (m, 3H,

H. _Ar .), 7.51-7.61 (m, 6H, H _{and Ar} ); M ⁺ (ESI ⁺ ): 407.31; M (ESI = 405.13).

- 72 · 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 (3Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazole- 5-yl] -3-pyrrolidinone O-methyloxime: white solid, mp 141 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): 2.98-3.05 (m, 3H, CH ₂ ), 3.33 (m, 1H, CH ₂ ), 3.86 (s, 3H, OCH ₃ ), 4.35-4.57 (m, 2H) CW ₂ ), 6.04 (m, 1H, CH), 7.38-7.51 (m, 3H, H _Ar ), 7.51-7.61 (m, 6H, H _Ar ); M ⁺ (ESI ⁺ ): 407.31. M (ESI): 405.13.

Example 10:

2- (5-f (2S, 4EZ) -1- (1'-biphenyl-4-ylcarbonyl) -4- (methoximino) pyrrolidinyl-1,2,4-oxadiazol-3-yl} ethyl) - (tert- 2- (5-f (25,4EZ) 1- (N, N-biphenyl-4-ylcarbonyl) -4-methoxy-pyrimidin-1-yl) -oxadiazole-Svl} ethyl aminoacetate.

To a stirred solution of (3Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] - 3-pyrrolidinone O-methyloxime (1.59mmol, Example 9), dimethylaminopyridine (185mg, 1.51mmol) and [(tert-butoxycarbonyl) amino] acetic acid (264mg, 1.51mmol) in DCM (50ml) at 0 ° C for EDC (290mg, 1.51mmol) was added in portions (over 15 minutes). After stirring for 1 hour at 0 ° C, the reaction mixture was allowed to warm to room temperature. The reaction mixture was monitored by TLC and LC / MS. After an additional hour of stirring at RT, the reaction mixture was hydrolyzed with water, washed with citric acid 10% (2 x 10ml) then Na ₂ CO 3 (aq) (2 x 10ml), dried over MgSO ₄ and evaporated in vacuo to give the crude product. Silica gel chromatography, eluting with 40% EtOAc in cyclohexane gave the title compound, (2- {5 - [(2S, 4EZ) -1 ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] - 1,2,4-oxadiazol-3-yl} ethyl [(tert-butoxycarbonyl) amino] acetate) as a mixture of E- and Z-isomers in 90% yield (HPLC purity: 93.6%).

«« · • • • • «* * * * * * ·« «« «« «« «« «« « · ♦ · ·· ·

- 73 M ^& lt ^{; +} & gt ^; (ESI &lt; ⁺ & gt ^; ): 564.61; M (ESI): 562.60 (2- {5 - [(2S, 4EZ) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazole -3-yl} ethyl [(tert-butoxycarbonyl) amino] acetate (100mg, 0.178 mmol) was treated with 25% TFA / DCM solution at 0 ° C for 1 hour. The reaction mixture was then basified slowly with sodium carbonate solution (10%) at 0 ° C and extracted with DCM. The organic phases were combined and dried over magnesium sulfate to remove the desired compound, 2- {5 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4 (methoxyimino) 1-pyrrolidinyl] -1,2,4-oxadiazol-3-yl} -ethylaminoacetate as an oil in 70% yield (94.6% HPLC purity).

M ⁺ (ESI &lt; ⁺ & gt ^; ): 464.17; M (ESL): 462.86

Example 11:

(3 EZ, 5 S) -1-f ^{(2'-chloro-4-fluoro} [1,1' -bifenvn-4-yl) carbonyl) -5- [3- (2-hvdroxvethyl) -1,2,4 oxadiazol-5-yne-3-pyrrolidinone O-methyloxime.

Following the general procedures outlined in Example 1 (Method B), (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), N ', 3-dihydroxypropanimidamide, (intermediate 7) and 2'-chloro-4'-fluoro [1,1'-biphenyl] -4-carboxylic acid (intermediate 10) after flash chromatography isolated the title compound as a mixture of E / Z isomers as an oil in 8% total yield (78.7% purity by HPLC).

Oil; 1 H NMR (300 MHz, CDCl ₃ ): 2.93 (m, 2H, CH ₂ ), 3.10-3.25 (m, 2H, CH ₂ ), 3.80 (s, 3H, NOCH 3), 4.34-4.45 (m, 2H, CH) ₂ ), 5.98 (m, 1H), 6.90-7.05 (m, 2H, aroma H), 7.20-7.66 (m, 5H, aroma H); MS (ESL) 459.12; MS (ESL) 457.07.

- 74 · · · · · »·» · »·» 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 · · · ·· ·

Example 12:

tert-Butyl-4- (5-f (2S, 4EZ) -1 - ([1,1'-biphenyl-4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl-1,2,4-oxadiazol-3-yl) -1- piperidinecarboxylate; (3EZ, 5S) -1- (1,1,1'-biphenyl-4-carbonyl) -5- [3- (4-piperidinyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone

O-methyloxime.

According to the general methods outlined in Example 1 (Method A), from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), tert-butyl 4- [ amino (hydroxyimino) methyl] -1-piperidinecarboxylate (intermediate 7) and [1,1'-biphenyl] -4-carbonyl chloride, after flash chromatography (cyclohexane / ethyl acetate 6/4), the title compound, tert-butyl 4- { 5 - [(2S, 4ZZ) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -4 (methoxyimino) -pyrrolidinyl] -1,2,4-oxadiazole-3 -yl} -1-piperidinecarboxylate, as a mixture of E / Z isomers in 60% yield (97.9% purity by HPLC).

Oil; ¹ H NMR (300 MHz, CDCl ₃ ): 1.47 (s, 9H, CH ₃ ), 1.60-2.10 (m, 4H, CH ₂ ), 2.90-3.02 (m, 2H, CH ₂ ), 3.30-3.40 (m , 1H, CH), 3.86 (s, 3H, NOC / Y), 4014.55 (m, 6H, _CH2 N), 6.03 (m, 1H), 7.48 to 7.64 (m, 9H, H arom.); MS (ESI &lt; ^{+ &} gt ^; ): 546.4; MS (ESI) 544.2.

tert-Butyl 4- {5 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazole-3- yl} -1-piperidinecarboxylate (100 mg, 1.80 mmol) was treated with 25% TFA / DCM solution at 0 ° C for 1 h. The reaction mixture was then basified with sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate

- 75 •>

• ·

Removal of the solvent gave a residue which was purified by flash chromatography using cyclohexane / ethyl acetate (2/8) as eluent to give (3EZ, 5S) -1 - ([1,1'-biphenyl] -4- ylcarbonyl) -5- [3- (4-piperidinyl) 1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime as a mixture of E / Z isomers in 80% yield (96.1% HPLC purity) .

Oil; ¹ H NMR (300 MHz, CDCl _3): 1.80 to 2.20 (m, 4H, _CH2), 2.90 to 3.50 (m, 8H, _CH2), 3.87 (s, 3H, NOC / 7 _3), 4.30 to 4.60 (m, 2H, _CH2), 6.04 (m, 1H, CH), 7487.64 (m, 9H, H arom.); MS (ESI ^&lt; ^{+ &} gt ^; ): 446.4.

Example 13:

(3EZ, 5S) -5- [3- (1-acetyl-4-piperidinyl) -1,2,4-oxadiazol-5-yl] -1- (1,1'-biphenyl-4-ylcarbonyl) -3-pyrrolidinone O -methyloxim.

(3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- [3- (4-piperidinyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O- methyloxime (Example 12) was dissolved in dry DCM at 0 ° C in the presence of 1.5 equivalents of triethylamine and treated with 1 equivalent of acetyl chloride. The reaction mixture was stirred at this temperature for 30 minutes and then hydrolyzed with ice. The reaction mixture was then basified with sodium carbonate solution (10%) and extracted with DMC. It was dried over magnesium sulfate and the solvent was removed to give a residue which was purified by flash chromatography using cyclohexane / ethyl acetate (1/1) as eluent to give (3EZ, 5S) -5- [3- (1-acetyl-4-piperidinyl)] -1,2,4-oxadiazol-5-yl] -1 - ([1,1,4] ·

76-Biphenyl] -4-ylcarbonyl-3-pyrrolidinone O-methyloxime as a mixture of E / Z isomers in 95% yield (100% HPLC purity).

Oil; 1 H NMR (300 MHz, CDCl ₃ ): 1.70-2.20 (m, 8H, CH ₃ CO, CH ₂ ), 2.89-3.40 (m, 6H, CH ₂ ), 3.88 (s, 3H, NOCH ₃ ), 4.40- 4.60 (m, 2H, _CH2), 6.04 (m, 1H, CH), 7.48 to 7.64 (m, 9H, H arom.); MS (ESI ^&lt; ⁺ &gt;);488.37; MS (ESI) 486.17.

Example 14:

(3EZ, 5S) -1 - ([1,1'-Biphenyl-4-ylcarbonyl) -5- [3- (1-methyl-4-piperidinyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone Q -methyloxim.

(3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- [3- (4-piperidinyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O- methyloxime (Example 12) was dissolved in dry DCM at 0 ° C in the presence of 1.5 equivalents of triethylamine and treated with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was hydrolyzed and then basified with sodium carbonate solution (10%) and extracted with DCM. It was then dried over magnesium sulphate and the solvent removed to give a residue which was purified by flash chromatography using dichloromethane / methanol (98/2) as eluent to give (3EZ, 5S) -1 - ([1,1'-biphenyl-1-4- ylcarbonyl) -5- [3- (1-methyl-4-piperidinyl) 1,2,4-oxadiazol-5-yl-3-pyrrolidinone O-methyloxime as a mixture of E / Z isomers in 50% yield (96.8% purity) HPLC).

Oil; ¹ H NMR (300 MHz, CDCl ₃ ): 1.19 (m, 2H, CH ₂ ), 2.14-2.70 (m, 8H, CH ₃ , CH ₂ ), 2.89-3.25 (m, 4H, CH ₂ ), 3.80 ( s, 3H, NOCH _3), 4.20 to 4.55 (m, 2H, _CH2);

5.94 (m, 1H, CH); 7.33-7.58 (m, 9H, aromatic H); MS (ESI &lt; ^{+ &} gt ^; ): 460.43; MS (ESI) 458.24.

Example 15:

A general method for synthesizing the dissolved phase of pyrrolidine oxadiazole derivatives of formula I wherein B is a substituent of formula IIb (see Schemes 7,11):

(3EZ, 5S) -1- (η 1,1'-biphenyne-4-carbonyl) -5-5- (phenoxymethyl) -1,2,4-oxadiazol-3-yl-3-pyrrolidinone O-methyl-oxime

To a suspension of (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8, 100mg, 0.28mmol) ,

DMAP (41mg, 0.34mmol) and phenoxyacetic acid (48mg, 0.31mmol) in DCM & DMF (1: 1, 10ml) were added EDO (59mg, 0.31mmol). After stirring overnight at ambient temperature, the solvent was evaporated in vacuo. The residue was dissolved in DCM (10ml) and washed with citric acid (aqueous) (2 x 10ml) followed by sodium bicarbonate (aqueous) (2 x 10ml). After evaporation in vacuo, pyridine (15ml) was added and the solution was refluxed overnight. The pyridine was removed in vacuo and the residue was dissolved in DCM (10ml), washed with citric acid (aqueous) (2 x 10ml), dried over magnesium sulphate and evaporated to give the title compound in 80% HPLC purity. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 469.2.

- 78 Example 16:

(3 - [(2S, 4EZ) -1 - ([1,1'-Biphenyl-4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl-1,2,4-oxadiazol-5-yl) methylformamide

Following the general procedure of Example 15, (2S, 4EZ) -1 - ([1,1-biphenyl] -4-ylcarbonyl) - N -hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and (formylamino) acetic acid obtained the title compound in 72% purity by HPLC.

¹ H-NMR (400MHz, CDCl ₃ ): 2.9-3.2 (m, 2H), 3.8 (m, 3H), 4.2-4.4 (m, 2H0, 4.6 (m, 2H), 5.9 (m, 1H), 7.0 (m, 1H), 7.3-7.7 (m, 9H), 8.2 (s, 1 H) MS (ESI ⁺ ): m / z = 420.1.

Example 17:

(3EZ, 5S) -1- (1,1,1-Biphenyl-4-carbonyl) -5- [5- (methoxymethyl) -1,2,4-oxadiazol-3-yn-3-pyrrolidinone O-methyloxime

• · · · · · · ·····

According to the general procedure of Example 15, (2S, 4EZ) -1 - ([1,1-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide ( Intermediate 8) and methoxyacetic acid obtained the title compound in 91% purity by HPLC.

¹ H-NMR (400MHz, CDCl ₃ ): 2.9-3.2 (m, 2H), 3.4 (s, 3H), 3.75 (m, 3H), 4.2-4.5 (m, 2H), 4.6 (s, 2H), 6.0 (m, 1H, 7.4-7.6 (m, 9H). MS (ESI ⁺ ): m / z = 407.2.

Example 18:

(3EZ, 5S) -1- (η 1,1'-biphenyl-4-carbonyl-5- (5-phenyl-1,2,4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and benzoic acid obtained the title compound in 85% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 439.2.

- 80 9 9 9

9 9 9 9 9

Example 19:

/ V - ({3-f (2S, 4EZ) -1- (ri, ^1, -bifenyn-4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl11,2,4-oxadiazol-5-yl) methyl) acetamide

According to the general procedure of Example 15, starting from (2S, 4ZZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate 8) and (acetylamino) acetic acid gave the title compound in 72% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 434.2.

Example 20:

(3 EZ, 5 S) -1 - ^([1,1, -bifenvl1-4-ylcarbonyl) -5- {5-í4- (hvdroxymethyl) -phenyl-1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O- methyloxim

According to the general procedure of Example 15, z (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximide ··· ·· ·· ·· ·

81 amide (intermediate 8) and 4- (hydroxymethyl) benzoic acid gave the title compound in 54% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 469.4.

Example 21:

(3EZ, 5S) -1 - ([1,1'-Biphenyl-4-ylcarbonyl) -5- [5- (2-hydroxyethyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and 3-hydroxypropanoic acid obtained the title compound in 61% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 407.2.

Example 22:

(3EZ, 5S) -1- (1,1,1-Biphenyne-4-carbonyl) -5- {5-r (2S) -2-hydroxy-2-phenylethyl-11H-oxadiazole-5-N-S-pyrrolidinone O-methyloxime

According to the general procedure of Example 15, (2S, 4ZZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximide 82 amide (intermediate 8) and (3S) -3-hydroxy-3-phenylpropanoic acid obtained the title compound in 89% purity by HPLC. MS (ESI ⁺ ) m / z = 483.3.

Example 23:

(3EZ, 5S) -1 - ([1,1'-Biphenyl-4-carbonyl) -5-F5- (2-phenoxyethyl) -1,2,4-oxadiazol-3-yl-3-pyrrolidinone O-methyloxime

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8) and 3-phenoxypropanoic acid gave the title compound in 84% purity by HPLC. MS (ESI ⁺ ) m / z = 483.3.

Example 24:

(3EZ, 5S) -1- (1,1'-Biphenyl-4-ylcarbonyl) -5-5- (2-methoxyethyl) -1,2,4-oxadiazole-3-yl-3-pyrrolidinone O-methyloxime

According to the general procedure of Example 15, (2S, 4ZZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximide - 83 -

The amide (intermediate 8) and 3-methoxypropanoic acid obtained the title compound in 80% HPLC purity. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 421.1.

Example 25:

(3EZ, 5S) -5- [5- (1-acetyl-4-piperidinyl) -1,2,4-oxadiazol-3-yl] -1- (1'-biphenyl-4-ylcarbonyl) -3-pyrrolidinone O-methyloxime

According to the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N -hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide ( Intermediate 8) and 1-acetyl-4-piperidinecarboxylic acid gave the title compound in 87% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 488.4.

Example 26:

(3 EZ, 5 S) -1 - ^([1,1, -bifenyH-4-ylcarbonyl) -5-5- (2-pyridinyl) -1 ^^ - oxadiazol-S-ylI3-pyrrolidinone O-methyloxime

According to the general procedure of Example 15, from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximide-84. • · * 4 · 4 4 · 4 4 «· · 4 · · 4 4 4 · ·«

4 4 4 4 4 · * * · ··· · · 4 · »···«

444 44 44 44 4 · · amide (intermediate 8) and 2-pyridinecarboxylic acid gave the title compound in 82% purity by HPLC. MS (ESI ⁺ m / z = 440.2).

Example 27:

(3EZ, 5S) -1- (F1,1'-Biphenyl-4-carbonyl) -5- [5- (3-thienyl) -1H-oxadiazol-5-yl] -pyrrolidinone O-methyloxime

Following the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and 3-thiophenecarboxylic acid gave the title compound in 64% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ). m / z = 445.2.

Example 28:

(3EZ, 5S) -1- (F1,1'-Biphenyl-4-ylcarbonyl) -5- (5-ethyl-1,2,4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime

Following the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8). ) and propionic acid gave the title compound in 47% purity by HPLC. MS (ESI ⁺ ): m / z = 391.1.

- 85 · · 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 ··· · · · · · ·

Example 29:

(3EZ, 5S) -1- (η 1 -biphenyl-4-carbonyl) -5- (5-cyclopentyl-1,2,4-oxadiazol-3-yl) 3-pyrrolidinone O-methyloxime

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and cyclopentanecarboxylic acid gave the title compound in 62% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 431.1.

Example 30:

(3CZ, 5S) -1- (1'-Biphenyl] -4-carbonyl) -5- (5-methyl-1,2,4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime

Following the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8). ) and acetic acid gave the title compound in 76% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 377.0.

- 86 • ·····························

Example 31:

(3EZ, 5S) -1 - ([1,1'-biphenyl-4-ylcarbonyl) -5- {5-r (RS) -hydroxy (phenyl) methyl-1,2,4 oxadiazol-3-yl} - 3-pyrrolidinone O-methyloxime

According to the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N -hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide ( Intermediate 8) and (2ES) -hydroxy (phenyl) ethanoic acid gave the title compound in 73% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 469.3.

Example 32:

(3EZ, 5S) -1- (1 H -biphenyl-4-carbonyl) -5- {5 - {(1 S) -1-hydroxy-2-phenylethyl] -1,2,4-oxadiazol-3-yl -3-pyrrolidinone O-methyloxime

Following the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8). ) and (2S) -2-hydroxy-3-phenylpropanoic acid gave the title compound in 78% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 483.3.

Example 33:

(3EZ, 5S) -1- (1,1'-biphenyl-4-carbonyl) -5-η 5 - (1 R) -1- (dimethylamino) -2-phenylethyl-1,2,4-oxadiazole- 3-yl} -3-pyrrolidinone O-methyloxime

According to the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N ^, -hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and (2R) -2- (dimethylamino) -3-phenylpropanoic acid gave the title compound in 54% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 510.6.

Example 34:

(3EZ, 5S) -1- (1,1'-biphenyl-4-ylcarbonyl) -5- [5- (3-pyridinyl) -1,2,4-oxadiazol-3-yl] -pyrrolidinone O-methyloxime

Following the general procedure of Example 15, (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and 3-pyridinecarboxylic acid gave the title compound in 78% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 440.2.

• * · ·· ·· · ·

- 88 Example 35:

(3EZ, 5S) -1 - ([1,1'-biphenyne-4-carbonyl) -5-F5- (6-hydroxy-3-pyridinyl) -1,2,4-oxadiazol-3-yn-3-pyrrolidinone O-methyloxime .

According to the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and 6-hydroxynicotinic acid gave the title compound in 50% yield (90% HPLC purity).

¹ H NMR (300 MHz, CDCl ₃ ): 2.90-3.30 (m, 2H, CH ₂ ), 3.86 (s, 3H, NOCH ₃ ), 4.30-4.60 (m, 2H, CH ₂ ), 6.04 (m, 1H) CH, 6.70 (d, 1H, aromatic H), 7.40-7.70 (m, 9H, aromatic H); 8.10 (d, 1H, aromatic H); 8.40 (d, 1H, aromatic H); MS (ESI &lt; ^{+ &} gt ^; ): 456.4; MS (ESI) 454.2.

Example 36:

(3EZ, 5S) -1 - ([1,1'-biphenyl-4-ylcarbonyl) -5- {5 - [(dimethylamino) methyn-1,2,4oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime ; (3Z, 5S) -1- (η 1,1'-biphenyl-4-ylcarbonyl) -5- {5-f (dimethylamino) methyl-1,2,4-oxadiazol-3-yl) -3-pyrrolidinone Omethyloxime; - (3E, 5S) -1- (1,1'-biphenyl-4-ylcarbonyl) -5- {5-f (dimethylamino) methyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime.

- 89 «89 89 89 89 89 89 89 89 89 89 89 89 89

According to the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N ^, -hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide ( Intermediate 8) and (dimethylamino) acetic acid gave the title compound in 50% overall yield (96% HPLC purity) as a mixture of E- and Zisomers. Separation by flash chromatography gave the pure Z-isomer in 23% yield (98.5% HPLC purity) and the pure E-isomer in 20% yield (98.2% HPLC purity).

(3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- {5 - [(dimethylamino) methyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O - methyl oxime: ¹ H NMR (300 MHz, CDCl ₃ ): 2.42 (s, 6H, CH ₃ ), 2.90-3.30 (m, 2H, CH ₂ ), 3.86 (s, 3H, NOCH ₃ ), 4.30-4.60 ( m, 2H, _CH2), 6.01 (m, 1H, CH), 7.40 to 7.70 (m, 9H, H arom.); MS (ESI ⁺ ), 420.4.

(3Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(dimethylamino) methyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O- methyloxime: ¹ H NMR (300 MHz, CDCl ₃ ): 2.42 (s, 6H, CH ₃ ), 2.90-3.30 (m, 2H, CH ₂ ), 3.86 (s, 3H, NOCH ₃ ), 4.30-4.60 (m , 2H, CH _2), 6.01 (m, 1H, CH), 7.40 to 7.70 (m, 9H, H arom.); MS (ESI ⁺ ), 420.4.

(3E, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- {5 - [(dimethylamino) methyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O - methyl oxime: ¹ H NMR (300 MHz, CDCl ₃ ): 2.42 (s, 6H, CH ₃ ), 2.90-3.30 (m, 2H, CH ₂ ), 3.86 (s, 3H, NOCH ₃ ), 4.30-4.60 ( m, 2H, _CH2), 6.01 (m, 1H, CH), 7.40 to 7.70 (m, 9H, H arom.); MS (ESI ⁺ ), 420.4.

Example 37:

4 - ({3-f (2S, 4EZ) -1 - ([1,1'-biphenyl-4-ylcarbonyl-4'-methoxymethylamino) pyrrolidinyl-1,2,4-oxadiazol-5-yl) methyl) -2,6-piperazinedione.

• · · · · · ·

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and (3,5-dioxo-1-piperazinyl) acetic acid gave the title compound in 55% yield (99.0% HPLC purity).

¹ H NMR (300 MHz, CDCl ₃ ): 2.80-3.30 (m, 2H, CH ₂ ), 3.61 (s, 4H, CH ₂ ), 3.86 (s, 3H, NOCH ₃ ), 4.09 (m, 2H, CH ₂₎ 4.30 to 4.60 (m, 2H, _CH2), 6.02 (m, 1H, CH), 7.42 to 7.75 (m, 9H, Harom), 8.56 (m, 1H, NH); MS (ESI ⁺ ), 489.20; MS (ESI) 487.17.

Example 38:

(3EZ, 5S) -1- (η 1,1'-biphenyl-4-ylarbonyl) -5- {5- [2- (dimethylamino) ethyl] -1,2,4oxadiazol-3-yl} -3-pyrrolidinone O- methyloxim.

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and N, N-dimethyl-3-alanine gave the title compound in 25% yield (91.5% purity by HPLC).

¹ H NMR (300 MHz, CDCl ₃ ): 2.31 (s, 6H, CH ₃ ), 2.80-3.40 (m, 6H, CH ₂ ), 3.88 (s, 3H, NOCH ₃ ), 4.30-4.60 (m, 2H) CH ₂ ), 6.03 (m, 1H, CH), 7.40-7.63 (m, 9H, aromatic H); MS (ESI ^&lt; ^{+ &} gt ^; ): 434.4.

Example 39:

tert-Butyl (4S) -4- (3-r (2S, 4EZ) -1 - ([1,1'-biphenyn-4-ylcarbonyl) -4- (methoxyimino) pyrrolidinesH-1,2,4-oxadiazole-5) -vl) -4- (tert-butoxycarbonyl) amino butanoate.

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8) and (2S) -5-tert-butoxy-2 - [(tert-butoxycarbonyl) amino] -5-oxopentanoic acid gave the title compound in 75% yield (78.9% HPLC purity).

¹ H NMR (300 MHz, CDCl ₃ ): 1.31 (s, 18H, CH ₃ ), 2.05-2.45 (m, 4H, CH ₂ ), 2.702.95 (m, 2H, CH ₂ ), 3.87 (s, 3H) , NOCH _3), 4.30 to 4.55 (m, 2H, _CH2), 5.10 (m, 1H, CH), 6.03 (m, 1H, CH), 7.40 to 7.63 (m, 9H, H arom.); MS (ESI ⁺ ), 620.3, MS (ESI), 618.3.

Example 40:

(3EZ, 5RS) -1- (η 1'-biphenyl-4-ylcarbonyl) -5- η 5 - (1-methyl-3-piperidinyl) -1,2,4oxadiazol-3-yne-3-pyrrolidinone O- methyloxim,

- 92 • · · · · · · · · · · · · · · · t ·

Following the general procedure of Example 15, (2S, 4EZ) -1 - ([1,1-biphenyl] -4-ylcarbonyl) - N -hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and 1-methyl-3-piperidinecarboxylic acid gave the title compound in 72% yield (99.2% HPLC purity).

¹ H NMR (300 MHz, CDCl ₃ ): 1.60-1.80 (m, 3H, CH, CH ₂ ), 2.05-2.15 (m, 2H, CH ₂ ), 2.33 (s, 3H, CH ₃ ), 2.92-3.22 (m, 6H, _CH2), 3.84 (s, 3H, NOCH _3), 4344.50 (m, 2H, _CH2), 6.01 (m, 1H, CH), 7.38 to 7.63 (m, 9H, H arom .); MS (ESI ^&lt; ⁺ &gt;); 460.5

Example 41:

OEZ.SSj-1-yl, 1'-biphenyl] -4-carbonyl] -5- [5- (1-methyl-4-piperidinyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O- methyloxim.

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8) and 1-methyl-4-piperidinecarboxylic acid gave the title compound in 85% yield (96.9% HPLC purity).

93 93 Ή NMR (300 MHz, CDCl ₃ ): 1.98-2.14 (m, 5H, CH, CH ₂ ), 2.32 (s, 3H, CH ₃ ), 2.89-3.20 (m, 6H, CH ₂ ), 3.86 ( s, 3H, NOCH _3), 4.34 to 4.50 (m, 2H, _CH2), 6.02 (m, 1H, CH), 7.38 to 7.63 (m, 9H, H arom.); MS (ESI ^&lt; ^{+ &} gt ^; ): 460.4

Example 42:

(3EZ, 5S) -1 - ([1,1'-biphenyl-4-carbonyl) -5- (5-vinyl-1,2,4-cyclohexan-3-yl) -3-pyrrolidinone O-methyloxime.

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximiamide (interm. 8). ) and acrylic acid was obtained in 20% yield (89.4% HPLC purity).

¹ H NMR (300 MHz, CDCl ₃ ): 2.85-3.15 (m, 2H, CH ₂ ), 3.78 (s, 3H, NOCH ₃ ), 4.28-4.44 (m, 2H, CH ₂ ), 5.89 (m, 2H) CH, 6.45 (d, 1H, CH), 6.58 (d, 1H, CH), 7.30-7.56 (m, 9H, aromatic H); MS (ESI ^&lt; ^{+ &} gt ^; ): 389.2.

Example 43:

tert-Butyl_ (3E) -3- {3-f (2S, 4EZ) -1 - ([1,1'-biphenyl-4-carbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazole- 5-yl) -1-piperidinecarboxylate; (3EZ, 5SV1 (1,1,1'-Biphenyl-4-ylcarbonyl) -5-5-f (3R) -piperidin-11,1,2,4-oxadazol-3-yl) -3-pyrrolidinoe O-methyloxime.

- 94 · · · 94 94 94 94 94 94 94 94 94 94 94

Following the general procedure outlined in Example 15, (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8) and (3R) -1- (tert-butoxycarbonyl) -3-piperidinecarboxylic acid, the title compound, tert -butyl (3 R) -3- {3 - [(2S, 4EZ) -1 - ([1,1 '] biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} -1-piperidinecarboxylate in 85% yield (96.5% HPLC purity).

MS (ESI ^&lt; ^{+ &} gt ^; ): 546.5.

tert -Sutyl (3ft) -3- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4 -oxadiazol-5-yl} -1-piperidinecarboxylate (100 mg, 1.80 mmol) was treated at 0 ° C with 25% TFA / DCM for 1 h. The reaction mixture was then basified with sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate and the solvent removed to give a residue which was purified by flash chromatography using dichloromethane / methanol as eluent to give the desired product, (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 [(3R) -piperidinyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime, as a mixture of E / Z isomers in 80 yield (95.7% purity by HPLC).

¹ H NMR (300 MHz, CDCl ₃ ): 1.62-1.92 (m, 3H, CH ₂ ), 2.20-2.42 (m, 2H, CH ₂ ),

2.75 to 3.41 (m, 7H, _CH2), 3.86 (s, 3H, NOCH _3), 4.36 to 4.51 (m, 2H, _CH2), 6.02 (m, 1H, CH), 7.40 to 7.64 (m, 9H , H arom); MS (ESI ^&lt; ⁺ &gt;); 446.2.

- 95 Φ «4 · · · · ·

Example 44:

(3C, 5S) -1- (1,1'-Biphenyn-4-ylcarbonyl) -5- {5-i (3P) -1-methylpiperidin-1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O -methyloxim.

A solution containing 1 equivalent of (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 [(3R) -piperidinyl] -1,2,4-oxadiazole-3- yl} -3-pyrrolidinone O-methyloxime (Example 43), dissolved in dry DCM at 0 ° C in the presence of 1.5 equivalents of triethylamine, was treated with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was hydrolyzed and then basified with sodium carbonate solution (10%) and extracted with DCM. The organic phase was then dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified by flash chromatography using dichloromethane / methanol as eluent to give the expected product, (3 EZ, 5 S) -1 - ([1,1'-biphenyl ^R] -4-ylcarbonyl) -5- {5 [(3R) -1-methylpiperidinyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime, as a mixture of the E / Z-isomers in 45 yield (97.6% purity by HPLC).

¹ H NMR (300 MHz, CDCl ₃ ): 1.61-1.90 (m, 3H, CH ₂ ), 2.01-2.20 (m, 3H, CH ₂ ), 2.23 (m, 3H, CH ₃ ), 2.70-3.30 (m 5H, CH ₂ ), 3.77 (s, 3H, NOCH ₃ ), 4.30-4.52 (m, 2H, CH ₂ ), 6.01 (m, 1H, CH), 7.38-7.70 (m, 9H, aromatic H) ; MS (EST): 460.2.

• · · · · ·

Example 45:

tert-butyl (3S) -3- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl-4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazole- (3EZ, 5S) -1- (1,1'-biphenyl-4-ylcarbonyl) -5- {5-r (3S) -piperidinyl-1,2,4-oxadiazole-3- (5-yl) -1-piperidinecarboxylate; yl} -3-pyrrolidinone O-methyloxime.

According to the general procedure of Example 15, starting from (2S, 4ZZ) -1 - ([1,1biphenyl] -4-ylcarbonyl) - N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide ( Intermediate 8) and (3S) -1- (tert-butoxycarbonyl) -3-piperidinecarboxylic acid gave the title compound, tert-butyl (3S) -3- {3 - [(2S, 4EZ) -1 - ([1,1] (biphenyl) -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} -1-piperidinecarboxylate in 85% yield (97.20% purity by HPLC).

MS (ESI ⁺ ): 546.5 tert-Butyl (3S) -3- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-Oxadiazol-5-yl} -1-piperidinecarboxylate (100 mg, 1.80 mmol) was treated with 25% TFA / DCM solution at 0 ° C for 1 h. The reaction mixture was then basified with sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate and the solvent removed to give a residue which was purified by flash chromatography using dichloromethane / methanol as eluent to give the desired product, (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(3S) -97-

piperidinyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime, as a mixture of EZZ-isomers in 85% yield (95.1% HPLC purity).

¹ H NMR (300 MHz, CDCl ₃ ): 1.62-1.92 (m, 3H, CH ₂ ), 2.20-2.42 (m, 2H, CH ₂ ), 2.75-3.41 (m, 7H, CH ₂ ), 3.86 (s , 3H, NOCH _3), 4.36 to 4.51 (m, 2H, _CH2), 6.02 (m, 1H, CH), 7.40 to 7.64 (m, 9H, arom H); MS (ESI ^&lt; ^{+ &} gt ^; ): 446.2.

Example 46:

(3EZ, 55) -1 - ([1,1'-Biphenyl-4-ylcarbonyl) -5- {5-η (35) -1-methylpiperidinyl-1,2,4oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime.

Solution containing 1 equivalent of (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 [(3S) -piperidinyl] -1,2,4-oxadiazole-3 3-Pyrrolidinone O-methyloxime (Example 45), dissolved in dry DCM at 0 ° C in the presence of 1.5 equivalents of triethylamine, was treated with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours. The reaction seed was hydrolyzed and then basified with sodium carbonate solution (10%) and extracted with DCM. The organic phase was then dried with magnesium sulfate and concentrated in vacuo to give a residue which was purified by flash chromatography using dichloromethane / methanol as eluent to give the expected product, (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(3S) -1-methylpiperidinyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime, as a mixture of E- / Zisomers in 55% yield (97.9% purity by HPLC).

¹ H NMR (300 MHz, CDCl ₃ ): 1.61-1.90 (m, 3H, CH ₂ ), 2.01-2.20 (m, 3H, CH ₂ ), 2.33 (m, 3H, CH ₃ ), 2.70-3.30 (m . 5H, CH _2), 3.84 (s, 3H, NOCH _3), 4.30 to 4.52 (m, 2H, _CH2), 6.01 (m, 1H, CH), 7.38 to 7.70 (m, 9H, arom. H) ; MS (ESI ^&lt; ^{+ &} gt ^; ): 460.2.

Example 47:

tert-Butyl 4- (2- (3-t (2S, 4EZ) -1- (1,1'-biphenyl-4-ylcarbonyl) -4- (methoxyimino) pyrrolidine-1,2,4-oxadiazole-5- (1) ethyl) -1-piperazinecarboxylate.

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and 3- [4- (tert-butoxycarbonyl) -1-piperazinyl] propanoic acid gave the title compound in 70% yield (78% purity by HPLC).

1 H NMR (300 MHz, CDCl ₃ ): 1.38 (s, 9H, CH ₃ ), 2.38 (m, 4H, CH ₂ ), 2.70-2.85 (m, 6H, CH ₂ ), 3.34 (m, 4H, CH ₂₎ ), 3.84 (s, 3H, NOCH _3), 4.23 to 4.42 (m, 2H, _CH2), 5.92 (m, 1H, CH), 7.19 to 7.53 (m, 9H, H arom.); MS (EST): 575.5.

Example 48:

tert-Butyl 4 - ({3-f (2S, 4EZ) -1- ^(L í1,1 -bifenyl'l-4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyll-1 ^^ - oxadiazol-S-yljmethyD- (3EZ, 5S) -1 ([1,1'-biphenyl-4-ylcarbonyl) -5- [5- (1-piperazinylmethyl) -1,2,4-oxadiazol-3-yne-3-pyrrolidinone O-] 1-piperazinecarboxylate; methyloxim.

- 99 ···························

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8 ) and [4- (tert-butoxycarbonyl) -1-piperazinyl] acetic acid gave the title compound, tert-butyl 4 - ({3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4ylcarbonyl) - 4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} methyl) -1-piperazinecarboxylate in 75% yield (88% purity by HPLC).

¹ H NMR (300 MHz, CDCl ₃ ): 1.38 (s, 9H, CH ₃ ), 2.38 (m, 4H, CH ₂ ), 2.70-2.85 (m, 4H, CH ₂ ), 3.34 (m, 4H, CH) _2), 3.84 (s, 3H, NOCH, 4.23 to 4.42 (m, 2H, _CH2), 5.92 (m, 1H, CH), 7.19 to 7.53 (m, 9H, H arom.); MS (ESI ⁺⁾ 561.5.

tert-Butyl 4 - ({3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazole-5 -yl} methyl) -1-piperazinecarboxylate (100 mg, 1.80 mmol) was treated with 25% TFA / DCM solution at 0 ° C for 1 h. The reaction mixture was then basified with sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate and the solvent removed to give a residue which was purified by flash chromatography using dichloromethane / methanol as eluent to give the desired product, (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5 (1-piperazinylmethyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime as a mixture of E / Z isomers in 85% yield (94.3) % purity by HPLC).

¹ H NMR (300 MHz, CDCl ₃ ); 2.50 (m, 4H, _CH2), 2.85 to 2.87 (m. 4H, CH _2), 3043.19 (m, 2H, _CH2), 3.76 (s, 5H, _{CH2, NOCH3),} 4.27 to 4.42 (m, 2H, _CH2), 5.94 (m, 1H, CH), 7.20 to 7.54 (m, 9H, H arom.); MS (ESI ^&lt; ^{+ &} gt ^; ): 461.2.

- 100 · ······························

Example 49:

(3EZ, 5S) -1 - ([1,1'-biphenyl-4-carbonyl) -5- {5 - [(4-methyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-3-yl] - 3-pyrrolidinone O-methyloxime: (3Z, 5S) -1- (1,1,1'-biphenyl-4-ylcarbonyl) -5- {5 - [(4-methyl-1-piperazinyl) -methylH, 2,4-oxadiazole- 3-yl) -3-pyrrolidinone O-methoxyvime.

A solution containing 1 equivalent of (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5 (1-piperazinylmethyl) -1,2,4-oxadiazol-3-yl] The 3-pyrrolidinone O-methyloxime (Example 48), dissolved in dry DCM at 0 ° C in the presence of 1.5 equivalents of triethylamine, was treated with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was hydrolyzed and then basified with sodium carbonate solution (10%) and extracted with DCM. The organic phase was then dried with magnesium sulfate and concentrated in vacuo to give a residue which was purified by flash chromatography using dichloromethane / methanol as eluent to give the expected product, (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 [(4-methyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime, as a mixture of E- / Z isomers 50% yield (99.9% HPLC purity). The pure Z-isomer could be separated by flash chromatography and obtained in 31% yield (98.9% HPLC purity).

(3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- {5 - [(4-methyl-1-piperazinyl) methyl] 1,2,4-oxadiazole-3 -yl} -3-pyrrolidinone O-methyloxime: ¹ H NMR (300 MHz, CDCl ₃ ): 2.32 (s, 3H, CH ₃ ), 2.50-3.20 (m, 10H, CH ₂ ), 3.78-3.92 (m, 5H, CH ₂ ; NOCH ₃ ),

- 101 -

4.27 to 4.45 (m, 2H, _CH2), 5.95 (m, 1H, CH), 7.32 to 7.57 (m, 9H, arom H); MS (ESI ^&lt; ^{+ &} gt ^; ): 475.2.

(3Z, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- {5 - [(4-methyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-3-yl } -3-pyrrolidinone O-methyloxime: ¹ H NMR (300 MHz, CDCl ₃ ): 2.32 (s, 3H, CH ₃ ), 2.50-3.20 (m, 10H, CH ₂ ), 3.78-3.92 (m, 5H, CH ₂ ; NOCH ₃ ), 4.27-4.45 (m, 2H, CH ₂ ), 5.95 (m, 1H, CH), 7.32-7.57 (m, 9H, aromatic H); MS (ESI ^&lt; ^{+ &} gt ^; ): 475.2.

Example 50:

(3EZ, 5S) -5- (5- [4- (4-acetyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-3-yl} -1- (1,1'-biphenyl-4-ylcarbonyl) - 3-pyrrolidinone O-methyloxime; (3Z, 5S) -5- {5- [4- (4-acetyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-3-yl} -1- (f,1,1 ') (biphenyl-4-ylcarbonyl) -3-pyrrolidinone O-methyloxime.

To a solution containing 1 equivalent of (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) 5- [5- (1-piperazinylmethyl) -1,2,4-oxadiazol-3-yl] 3-Pyrrolidinone O-methyloxime (Example 48) in dry DCM, at 0 ° C was added 1.5 equivalents of triethylamine and 1 equivalent of acetyl chloride. The reaction mixture was stirred at this temperature for 30 minutes and then hydrolyzed with ice. The reaction mixture was then basified with sodium carbonate solution (10%) and extracted with DCM. The organic phase was dried with magnesium sulfate and the solvent was removed to give a residue which was purified by flash chromatography to give the expected product, (3EZ, 5S) -5- {5-f (4-acetyl-1-piperazinyl) methylene-1,2,4 -oxadiazol-3-yl (1,1-1,1'-biphenyl-4-ylcarbonyl) -3-pyrrolidinone Q-methyloxime as a mixture of E-Z-102 · Isomers in 70% yield (94.4% HPLC purity). The pure Z-isomer could be separated by flash chromatography using cyclohexane / ethyl acetate (1/1) as eluent and obtained in 40% yield (98.0% HPLC purity).

(3EZ, 5S) -5- {5-f (4-acetyl-1-piperazinyl) methyl-1,2,2-oxadiazol-3-yl) -1 - ([1,1'-biphenyl-4-ylcarbonyl] - 3-pyrrolidinone O-methyloxime: ¹ H NMR (300 MHz, CDCl 3): 2.09 (m, 3H, CH ₃ ), 2.65 (s, 4H, CH ₂ ), 2.90-3.20 (m, 2H, CH ₂ ), 3.54 (m, 2H, _CH2), 3.71 (m, 2H, CH _2), 3.85 to 3.92 (m, 5H, _{CH2; NOCH3),} 4.36 to 4.50 (m, 2H, _CH2), 6.02 (m, 1H, CH), 7.40-7.75 (m, 9H, arom arom) MS (ESP): 503.2.

(3Z, 5S) -5- {5 - [(4-acetyl-1-piperazinyl) methyl-1,2,4-oxadiazol-3-yl) -1 - ([1,1'-biphen-4-ylcarbonyl)] -3-pyrrolidinone O-methyloxime: ¹ H NMR (300 MHz, CDCl ₃ ): 2.09 (m, 3H, CH ₃ ), 2.65 (s, 4H, CH ₂ ), 2.90-3.20 (m, 2H, CH ₂ ) , 3.54 (m, 2H, _CH2), 3.71 (m, 2H, CH _2), 3.85 to 3.92 (m, 5H, _{CH2; NOCH3),} 4.36 to 4.50 (m, 2H, _CH2), 6.02 ( m, 1H, CH), 7.40-7.75 (m, 9H, arom arom); MS (ESP): 503.2.

Example 50:

4- {f (2S, 4EZ) -2- (5-f (tert-butoxycarbonyl) aminomethyl} -1H-oxadiazol-5-yl) -4- (methoxyimino) pyrrolidinecarbonyl) -1,1'-biphenyl.

According to the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (intermediate) 8) and [(tert-butoxycarbonyl) amino] acetic acid gave the title compound in 80% yield (78.2% HPLC purity).

- 103 ¹ H NMR (300 MHz, CDCl _3): 1.48 (s, 9H, _CH3), 1.58 (s, 2H, _CH2), 2.90 to 3.43 (m, 2H, _CH2), 3.85 (s, 3H NOC / 7 _3), 4.20 to 4.60 (m, 2H, _CH2), 6.03 (m, 1H, CH), 7.37 to 7.63 (m, 9H, H arom.); MS (ESI ⁺ ): 492.20, MS (ESI ⁺ : 490.2).

Example 51:

N - ((3-f (2S, 4EZ) -1- (f, T-biphenyn-4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl-1,2,4-oxadiazol-5-yl) methyl) -3 - (1-piperidinyl) propanamide.

4 - {[(2S, 4EZ) -2- (5 - {[(tert-butoxycarbonyl) amino] methyl} -1,2,4-oxadiazol-3-yl) 4- (methoxyimino) pyrrolidinyl] carbonyl} -1 1,1'-biphenyl (Example 50) was treated with 25% TFA / DCM solution at 0 ° C. The reaction was monitored by LC / MS until complete. The reaction mixture was basified with sodium carbonate solution (10%) and DCM. The combined oragnic phases were dried over magnesium sulfate. The solvent was removed to give the crude product, which was used without further purification in the next step. The residue was dissolved in DCM at room temperature, DMAP (1.1 equivalent) and 3- (1-piperidinyl) propanoic acid (1 equivalent) were added. The reaction mixture was then cooled to 0 ° C and EDC (1.1 equivalents) was added portionwise. After stirring for 1 hour at 0 ° C, the reaction mixture was allowed to warm to room temperature. The reaction mixture was monitored by TLC and LC / MS. Typically, after stirring at room temperature for 12 hours, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO ₄ and evaporated in vacuo to give the crude product. Flash chromatography on silica gel, eluting with 60% EtOAc in hexane

- 104 -

to give the title compound as a mixture of E- and Z-isomers in 50% yield (87.4% purity by HPLC).

MS (ESI &lt; ^{+ &} gt ^; ): 531.5; MS (ESI) 529.2.

Example 52:

N - ((3-f (2S, 4EZ) -1 - ([1,1'-biphenvl-4-ylcarbonyl) -4- (methoxvimino) pyrrolidinyl-1,2,4-oxadiazol-5-yl) methyl) - 3- (dimethylamino) propanamide.

4 - {[(2S, 4EZ) -2- (5 - {[(tert-butoxycarbonyl) amino] methyl} -1,2,4-oxadiazol-3-yl) 4- (methoxyimino) pyrrolidinyl] carbonyl} -1 1,1'-biphenyl (Example 50) was treated with 25% TFA / DCM solution at 0 ° C. The reaction was monitored by LC / MS and stopped after completion. The reaction mixture was then basified with sodium carbonate solution (10%) and extracted with DCM. The combined oragnic phases were dried over magnesium sulfate. The solvent was removed to give the crude product, which was used without further purification in the next step. The residue was dissolved in DCM at room temperature, DMAP (1.1 equivalent) and N, N -dimethyl-β-alanine (1 equivalent) were added. The reaction mixture was then cooled to 0 ° C and EDC (1.1 equivalents) was added portionwise. After stirring for 1 hour at 0 ° C, the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC / MS. Typically, after stirring at room temperature for 12 hours, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO ₄ and evaporated in vacuo to give the crude product. Flash chromatography on silica gel,

- 105 -

elution with 60% EtOAc in hexane gave the title compound as a mixture of E- and Zisomers in 52% yield (82% purity by HPLC).

MS (ESI ^&lt; ^{+ &} gt ^; ): 491.2.

Example 53:

N - ({3- (2S, 4EZ) -1 - ([1,1'-biphenyne-4-carbonyl) -4- (methoxyimino) pyrrolidinyl-1,2,4-oxadiazol-5-yl} -methyl- 2- (dimethylamino) acetamide.

4 - {[(2S, 4EZ) -2- (5 - {[(tert-butoxycarbonyl) amino] methyl} -1,2,4-oxadiazol-3-yl) 4- (methoxyimino) pyrrolidinyl] carbonyl} - 1,1'-Biphenyl (Example 50) was treated with 25% TFA / DCM solution at 0 ° C. The reaction was monitored by LC / MS and monitoring stopped after completion. The reaction mixture was then basified with sodium carbonate solution (10%) and extracted with DCM. The combined organic phases were dried over magnesium sulfate. The solvent was removed to give the crude product, which was used without purification in the next step. The residue was dissolved in DCM at room temperature, DMAP (1.1 equivalents) and (dimethylamino) acetic acid (1 equivalents) were added. The reaction mixture was then cooled to 0 ° C and EDC (1.1 equivalents) was added portionwise. After stirring at 0 ° C for one hour, the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC / MS. Typically, after stirring at room temperature for 12 hours, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO ₄ and evaporated in vacuo to give the crude product. Flash chromatography on silica gel, eluting with 60% EtOAc in hexane, afforded the title compound as a mixture of E- and Zisomers in 45% yield (88.1% HPLC purity).

· E e e e e e e · · · * * * * e e e e e e e e

- 106

MS (ESI ⁺ ), 477.25: MS (ESI), 475.15.

Example 54:

4 - {[(2S, 4EZ) -2- (5- {2-f (tert -butoxycarbonyl) amino] ethyl} -1H-oxadiazol-S-yl) 4- (methoxvimino) pyrrolidinylcarbonyl) -1,1 biphenyl.

Following the general procedure outlined in Example 15, starting from (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8) and N - (tert -butoxycarbonyl) -β-alanine gave this compound in 75% yield (91.9% purity by HPLC).

¹ H NMR (300 MHz, CDCl ₃ ): 1.36 (s, 9H, CH ₃ ), 2.80-3.15 (m, 4H, CH ₂ ), 3.51 (m, 2H, CH ₂ ), 3.78 (s, 3H, NOCH) ₃₎ 4.27 to 4.42 (m, 2H, _CH2), 5.93 (m, 1H, CH), 7.39 to 7.56 (m, 9H, H arom.); MS (ESI ^&lt; ^{+ &} gt ^; ): 506.20, MS (ESL): 504.2.

Example 55:

4-ff (2S _l 4EZ) -2- (5-f (1 S) -2-tert-butoxy-1-t (tert-butoxycarbonyl) amino1ethyl) 1,2,4-oxadiazol-3-yl) -4- (methoxyimino (pyrrolidinylcarbonyl) -1,1'-biphenyl;

(3EZ, 5S) -5- {5 - [(1S) -1-amino-2-tert-butoxyethyl] -1H-oxadiazol-5-yl] -1,1-biphenyl-4-ylcarbonyl) -3-pyrrolidinone O-methyloxime; (3EZ, 55) -5- {5-f (15) -1-amino-2-hydroxyethyl-1,2,4-oxadiazol-3-yl} -1- (1'-biphenyl-4-ylcarbonyl) -3-pyrrolidinone O-methyloxime.

- 107 M and Λ Λ Λ w • w 9

According to the general procedure of Example 15, (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide ( Intermediate 8) and (2S) -3-tert-butoxy-2 - [(tert-butoxycarbonyl) amino] propanoic acid gave the title compound, 4 - {[(2S, 4EZ) -2- (5 - {(1S) -2- tert-butoxy-1 - [(tert-butoxycarbonyl) amino] ethyl} -1,2,4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinylf] carbonyl} -1,1'-biphenyl, in 44% yield (89.4% HPLC purity).

MS (ESI ^&lt; ^{+ &} gt ^; ): 578.5.

4 - {[(2S, 4EZ) -2- (5 - {(1S) -2-tert-butoxy-1 - [(tert-butoxycarbonyl) amino] ethyl} 1,2,4-oxadiazol-3-yl -4- (methoxyimino) pyrrolidinyl] carbonyl} -1,1'-biphenyl (100 mg, 1.80 mmol) was treated with 25% TFA / DCM solution at 0 ° C for 1 h. The reaction mixture was basified with sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate, and the solvent was removed to give two products which were separated and purified by flash chromatography to give the desired products as a mixture of E / Z isomers, (3EZ, 5S) -5- {5 - [( 1S) -1-amino-2-tert-butoxyethyl] -1,2,4-oxadiazol-3-yl} -1 - ([1,1-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime, ve 20% yield (80.8% HPLC purity), and (3EZ, 5S) -5- {5 - [(1S) -1-amino-2-hydroxyethyl] -1,2,4-oxadiazol-3-yl} -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime in 30% yield (98.1% purity by HPLC).

(3EZ, 5S) -5- {5 - [(1S) -1-amino-2-tert-butoxyethyl] -1,2,4-oxadiazol-3-yl} -1 - ([1,1 'biphenyl] 4-ylcarbonyl) -3-pyrrolidinone O-methyloxime: ¹ H NMR (300 MHz, CDCl ₃ ): 1.07 (s, 9H, CH ₃ ), 1.96 (m, 2H, NH ₂ ), 2.83-3.18 (m, 2H, CH ₂ ), 3.64

- 108 -

3.78 (m, 5H, _{CH2, NOCH3),} 4.23 to 4.43 (m, 2H, _CH2), 5.96 (m, 1H, CH), 7307.56 (m, 9H, arom H); MS (ESI ⁺ ), 478.0.

(3EZ, 5S) -5- {5 - [(1S) -1-amino-2-hydroxyethyl] -1,2,4-oxadiazol-3-yl} -1 - ([1,1 'biphenyl] -4 -ylcarbonyl) -3-pyrrolidinone O-methyloxime: ¹ H NMR (300 MHz, CDCl ₃ ): 2.90-3.15 (m, 2H, CH ₂ ), 3.86 (s, 3H, NOCH ₃ ), 4.05-4.42 (m, 4H, _CH2), 4.81 (m, 1H, CH), 5.89 (m, 1H, CH), 7.36 to 7.62 (m, 9H, arom H); MS (ESI ⁺ ): 422.20; MS (ESI -): 420.1.

Example 56:

4 - {[(2S, 4EZ) -2- (5 - ((1S, 2R) -2-tert-butoxy) -1- (tert-butoxycarbonyl) amino] propyl-1,2,4-oxadiazol-3-yl -4- (methoxvimino) pyrrolidine-1-carbonyl) -1,1'-biphenyl; (3EZ, 5S) -5- {5-f (1S, 2R) -1-amino-2-hydroxypropyl-1,2,4-oxadiazol-3-yl} -1 - ([1,1'-biphenyl-4- (carbonyl) -3-pyrrolidinone O-methyloxime.

Following the general procedure of Example 15, starting from (2S, 4EZ) -1 - ([1,1-biphenyl] -4-ylcarbonyl) - N '-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8 ) and (2S, 3R) -3-tert-butoxy-2 - [(tert-butoxycarbonyl) amino] butanoic acid gave the title compound, 4 - {[(2S, 4EZ) -2- (5 {(1S, 2 / (R) -2-tert-butoxy-1 - [(tert-butoxycarbonyl) -amino] -propyl} -1,2,4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl] carbonyl} -1, Γ -biphenyl, in 48% yield (85.9% purity by HPLC).

MS (ESI ⁺ ), 592.7

- 109 -

4 - {[(2S, 4EZ) -2- (5 - {(1S, 2R) -2-tert-butoxy-1 - [(tert-butoxycarbonyl) amino] petroleum} -1,2,4-oxadiazole -3-yl) -4- (methoxyimino) pyrrolidinyl] carbonyl} -1,1'-biphenyl (100 mg, 1.80 mmol) was treated with a 25% TFA / DCM solution at 0 ° C for 1 h. The reaction mixture was then basified with sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate, and the solvent was removed to give a residue which was purified by flash chromatography using dichloromethane / methanol as eluent to give the desired product, (3EZ, 5S) -5- {5 - [(1S) (2R) -1-amino-2-hydroxypropyl] -1,2,4-oxadiazol-3-yl} -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime, as a mixture of E- Of the Z-isomers in 30% yield (90.3% HPLC purity).

¹ H NMR (300 MHz, CDCl ₃ ): 1.24-1.35 (m, 4H, CH ₃ , CH), 2.94-3.25 (m, 2H, CH ₂ ), 3.83 (s, 3H, NOCH ₃ ), 4.22-4.50 (m, 3H, OH, CH ₂ ), 6.01 (m, 1H, CH), 7.38-7.60 (m, 9H, arom arom); MS (ESI ^&lt; ⁺ &gt;); 436.3.

Example 57:

Ethyl 5-f (2S, 4EZ) -1- (1,1,1-biphenyl-4-carbonyl) -4- (methoxyimino) pyrrolidinyl-1,2,4-oxadiazole-3-carboxylate.

o ^x i

According to the general procedure of Example 1 (Method B), from (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), ethyl amino (hydroxyimino) of ethanoate (intermediate 7) and [1,1'-biphenyl] -4-carboxylic acid after flash chromatography isolated the title compound as a mixture of the E / Z isomers as an oil in 35% yield (96.1% HPLC purity).

- 110 -

¹ H NMR (300 MHz, CDCl ₃ ): 1.35 (t, 3H), 2.9-3.3 (m, 2H), 3.8 (m, 3H), 4.2-4.60 (m, 4H), 6.01 (s, 1H), 7.25-7.60 (m. 9H); MS (ESI ^&lt; ^{+ &} gt ^; ): 435.3.

Example 58:

5-f (2S, 4EZ) -1- (t1-Biphenyl-4-carbonyl) -4- (methoxyimino) pyrrolidine-N- [3 (dimethylamino-propyl) -1H-oxadiazole-5-carboxamide.

Ethyl 5 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazole-3-carboxylate (187mg, 0.43mmol) Example 57) was dissolved in a 3: 1 ratio of THF: water (10ml) and stirred. LiOH (20mg, 0.47mmol, 1.1eq) was added and the mixture was stirred for 2 hours at room temperature. THF was removed in vacuo, the residue was diluted with water and the solution was acidified with 6N HCl (2 drops, pH = 5). The aqueous phase was extracted with DCM (2 x 10mL). The organic phase was dried with magnesium sulfate and the solvent was removed in vacuo to give the acid derivative (165mg, 94%) as a yellow oil. This crude intermediate (102mg, 0.25mmol) was dissolved in DCM (5mL) and the mixture was cooled to 0 ° C. EDC.HCl (53mg, 0.28mmol, 1.1eq) was added in one portion and the mixture was stirred for 10 minutes. Was added Λ / ¹ / V ¹ -dimethyl-1,3-propanediamine (35mg, 0.28mmol, 1.1ekv) and the solution was stirred at room temperature overnight. The mixture was then washed with 10% aqueous citric acid solution (2 x 5mL). The separation was not good due to the partial solubility of the compound in water. The organic solvent was removed in vacuo and the residue was purified by semi-preparative LC to give the title compound in 56% yield (93% purity by HPLC).

• · · ·

¹ H NMR (300 MHz, CDCl ₃ ): 2.0-2.1 (m, 2H), 2.8 (s, 6H), 2.9-3.3 (m, 4H), 3.5 (m, 2H), 3.8 (m, 3H) 4.2-4.60 (m, 4H); 5.9 (s, 1H); 7.25-7.65 (m, 9H); 7.8 (m, 1H); MS (ESI ^&lt; ^{+ &} gt ^; ): 491.4.

Example 59:

General method for solid phase synthesis of pyrrolidine oxadiazole derivatives of formula I wherein B is a substituent of formula IIa (see Scheme 13)

a) Filling step

A solution of (2S, 4EZ) -1- (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2, 26g, 100mmol) in dry DCM (150ml) was added to Kaiser oxime resin (34.97g, 50mmol) ), which was suspended in dry DCM (200ml). Diisopropylcarbodiimide (7.83ml, 50mmol) was then added to the suspension and the mixture was shaken overnight at ambient temperature. The resin was then filtered through a pump and subsequently washed with DMF, DCM and finally with diethyl ether before being dried at 40 ° C under vacuum.

b) Protection Removal Step

The resin obtained in the filling step was shaken with a 20% solution of trifluoroacetic acid in dichloromethane (200ml) 30 minutes before filtering with a pump followed by rinsing with aliquots of DMF, DCM and finally diethyl ether before drying at room temperature in vacuo.

c) Closure step

The resin from the previous step was transferred to 96-well filter plates (approximately 50 mg dry resin per well) and each well was treated with an N-reactive derivatizing agent, such as one of the following solutions:

a) acid chloride (0.165mmol) and diisopropylethylamine (0.165mmol) in dry dichloromethane (1 ml) overnight

- 112 (b) acid (0.165mmol) and DIC (0.165mmol) in dry dichloromethane or NMP (1 ml), depending on the solubility of the carboxylic acid, overnight

c) isocyanate (0.165 mmol) in dry THF (1 mL) overnight

d) sulfonyl chloride (0.165mmol) and diisopropylethylamine (0.165mmol) in NMP (1ml), overnight

e) benzyl (alkyl) bromide (0.165mmol) and diisopropylethylamine (0.165mmol) in NMP (1ml) overnight.

The plate was then sealed and shaken overnight at ambient temperature. The resins were then filtered and subsequently washed with aliquots of DMF, DCM and finally diethyl ether before drying at room temperature under vacuum.

d) Step of cleavage

The amidoxime component (e.g., intermediates 7, 0.27mmol) was added to the suspensions of the functionalized oxime resin feed from the previous step (50mg, 0.05 mmol) in DCM (0.5-1 mL), the plates were sealed and shaken over the weekend (~ 66 hours) at ambient temperature. After filtration, the resulting solvent was evaporated in vacuo. Pyridine (0.5-1 mL) was added to the residue and the solution was refluxed overnight. After cooling to ambient temperature, the solution was evaporated in vacuo and the residues redissolved in DMC (0.5-1ml). After washing with 2 x 0.5-1ml 1M HCl _(VO d), the solutions were dried over magnesium sulfate and evaporated in vacuo to give crude products which were analyzed by HPLC and mass spectroscopy. Where případech-Boc protecting group was present on the oxadiazole substituent (eg Examples 40, 46-48), a solution of 25% TFA in DCM (3ml) (usually 0.15mmol) was added to the crude compound and the solution was stirred at ambient temperature. temperature 40 minutes. The solvent was then removed in vacuo to give unprotected N products.

- 113 Example 60:

(3S, 5S) -5- (3-Benzyl-1,2,4-oxadiazol-5-yl) -1- (1'-biphenyl-4-carbonyl) -3-pyrrolidinone O-methyloxime

According to the general procedure of Example 59, starting from (2S, 45Z) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and N -hydroxy-2-phenylethanimidamide obtained the title compound in 86% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 453.2.

Example 61:

(3EZ, 5S) -1 - ([1,1'-biphenyl-4-ylcarbonyl) -5- (3 - ([(2-furlmethyl) sulfanylmethyl) 1,2,4-oxadiazol-5-yl) -3 -pyrrolidinone O-methyloxime

According to the general procedure of Example 59, starting from (2S, 4ZZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrophidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] - Of 4-carbonyl chloride and 2 - [(2-furylmethyl) sulfanyl] - N -hydroxyethanimidamide gave the title compound in 53% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 489.6.

• ·

- 114 Example 62:

(3EZ, 5S) -1- (1,1'-biphenyl-4-carbonyl) -5- (3- (2-oxo-2- (1-pyrrolidinyl) ethyl) -1,2,4-oxadiazol-5-yl) -3 - pyrrolidinone O-methyloxime

According to the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and (1Z) -N'-hydroxy-3-oxo-3- (1-pyrrolidinyl) propanimidamide gave the title compound in 89% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 474.2.

Example 63:

(3EZ.55) -1- _(1'-L f1 bifenyn-4-ylcarbonyl) -5- {3-f (2-pyridinylsulfanyl) methyl11,2.4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime

- 115 Following the general procedure outlined in Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] - 4-carbonyl chloride and N '-hydroxy-2- (2-pyridinylsulfanyl) ethanimidamide obtained the title compound in 66% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 486.2.

Example 64:

(3'Z, 5S) -1- (n, 1'-Biphenyl-4-carbonyl) -5- [3- (4-fluorophenyl) -1,2,4-oxadiazole-5-i-3-pyrrolidinone O-methyloxime

According to the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and 4-fluoro- N -hydroxybenzenecarboximidamide gave the title compound in 79% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 457.2.

Example 65:

(3EZ, 5S) -1- (1,1,1'-Biphenyl-4-carbonyl) -5- {3-r (2-thienylsulfanyl) methyl-1,2,4-oxadiazole-5-yl-S-pyrrolidinone O-methyloxime

According to the general procedure of Example 59, from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4 of carbonyl chloride and N '-hydroxy-2- (2-thienylsulfanyl) ethanimidamide gave the title compound in 81% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 491.4.

Example 66:

(3EZ, 5S) -1- (F1,1'-Biphenyl-4-carbonyl) -5- {3- [2- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -2,4-oxadiazol-5-yl -3-pyrrolidinone O-methyloxime?

According to the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and 3- (3,5-dimethyl-1H-pyrazol-1-yl) - N -hydroxypropanimidamide gave the title compound in 79% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 485.3.

Example 67:

(3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-carbonyl) -5- (3- (methylsulfonyl) methyl) -1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O- methyloxim • ·

- 117 -

Following the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and N'-hydroxy-2- (methylsulfonyl) ethanimidamide obtained the title compound in 87% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 455.2.

Example 68:

(3EZ, 5S) -1- (η 1'-biphenyl-4-ylcarbonyl) -5- 3- (5-methyl-3-isoxazolyl) -1,2,4-oxadiazole-5-yl-3-pyrrolidinone O- methyloxim

Following the general procedure outlined in Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and N'-hydroxy-5-methyl-3-isoxazolecarboximidamide gave the title compound in 78% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 444.2.

Example 69:

(3 EZ, 5 S) -1- (F1,1 -bifenyl1-4 ^{l-ylcarbonyl)} -5- [3- (2-thienvlmethyl) -1,2,4-oxadiazol-5-vH-3-pyrrolidinone O-methyloxime

- 118 -

According to the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and N -hydroxy-2- (2-thienyl) ethanimidamide gave the title compound in 85% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 459.2.

Example 70:

(3EZ, 5S) -1 - ([1,1'-Biphenyl-4-ylcarbonyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime

According to the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and N-hydroxybenzenecarboximidamide gave the title compound in 82% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 439.2.

Example 71:

(3EZ, 5S) -1- (1,1,1'-Biphenyl-4-ylcarbonyl) -5- (3- {1- (2-furylmethyl) sulfonylmethyl} 1,2,4-oxadiazol-5-yl) -3- pyrrolidinone O-methyloxime

- 119 -

According to the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and 2 - [(2-furylmethyl) sulfonyl] -N'-hydroxyethanimidamide gave the title compound in 88% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 521.4.

Example 72:

(3EZ, 5S) -5- [3- (aminomethyl) -1,2,4-oxadiazol-5-yl] - (1,1,1-biphenyl-4-ylcarbonyl) -3-pyrrolidinone O-methyloxime

According to the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and tert-butyl (2Z) -2-amino-2- (hydroxyimino) ethylcarbamate (intermediate 7) gave the title compound in 85% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 392.0.

Example 73:

(3EZ, 5S) -1 - ([N-biphenyl] -4-ylcarbonyl-5-O-1 H -hydroxyphenyl-4-methyl-1,2,4-oxadiazol-5-yl} -3-ovrolidinone O-methyloxime

- 120 z

O

N

According to the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and (2S) - N ', 2-dihydroxy-2-phenylethanimidamide (interm. 7) gave the title compound in 75% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 469.3.

Example 74:

(3 EZ, 5 S) -1- (ri, ^1, -bifenyn-4-ylcarbonyl) -5- {3-f (1 /? S) -1-hvdroxypropyn-1,2,4-oxadiazol-5-yl) -3 -pyrrolidinone O-methyloxime o

N

OH

According to the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and (2RS) - N ', 2-dihydroxybutanimidamide (intermediate 7) gave the title compound in 79% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 421.2.

(3EZ, 5S) -1- (n, 1'-Biphenyl-4-carbonyl) -5- [3- (hydroxymethyl) -1,2,4-oxadiazole-5-yl-3-pyrrolidinone O-methyloxime

Example 75:

Following the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and N, 2-dihydroxyethanimidamide (interm. 7) gave the title compound in 85% HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 393.0.

- 122 Example 76:

(3EZ, 5S) -1 - ([1,1'-biphenyl-4-carbonyl) -5- {3-f (1S, 2P) -2-hydroxycyclohexyl];

1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime

According to the general procedure of Example 59, (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate

2), [1,1'-biphenyl] -4-carbonyl chloride and (1S, 2R) - N ', 2-dihydroxycyclohexanecarboximidamide (intermediate 7) gave the title compound in 85% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 461.2.

Example 77:

(3EZ, 5S) -1 - ([1,1'-Biphenyl-4-carbonyl) -5- (3- | (3ES) -piperidin-11,1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O- methvloxim

According to the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate)

2), [1,1'-biphenyl] -4-carbonyl chloride and tert-butyl (3ES) -3- [amino (hydroxyimino) methyl] -1-piperidinecarboxylate (interm. 7) gave the title compound in 77% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 446.2.

- 123 -

· · · · * * * * «« «« «« ««

Example 78:

(3EZ, 5S) -1- (1,1'-biphenyl-4-ylcarbonyl) -5- {3-f (2S) -piperidines-1,2,4oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime

Following the general procedure of Example 59, starting from (2S, 4EZ) -1 (tert-butoxycarbonyl) -4- (methoxyimino) -2-pyrrolidinecarboxylic acid (intermediate 2), [1,1'-biphenyl] -4- carbonyl chloride and tert-butyl (2RS) -2- [amino (hydroxyimino) methyl] -1-piperidinecarboxylate (interm. 7) gave the title compound in 78% purity by HPLC. MS (ESI ^&lt; ^{+ &} gt ^; ): m / z = 446.2.

Example 79:

General method for the synthesis of the dissolved phase of pyrrolidine oxadiazole derivatives of the general formula I, wherein B is a substituent of the formula III, X = S (scheme 9,11):

(3EZ, 5S) -1- (η 1, T-biphenyn-4-ylcarbonyl) -5- (5-thioxo-4,5-dihydro-1,3,4oxadiazol-2-yl) -3-pyrrolidinone O-methyloxime

To a solution of tert-butyl (2S, 4EZ) -2- (hydrazinocarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylate (intermediate 9, 2.86 mmol; 780mg) in ethanol (25ml) was added.

- 124 -

at 0 ° C, carbon disulfide (6.86mmol; 522mg) and potassium hydroxide (3mmol; 168mg) were added. The mixture was refluxed for 7 hours. The solvent was evaporated and the residue was redissolved in EtOAc and washed with sat. NH ₄ Cl and 10% NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated to give the desired protected N, tert -butyl (2S, 4ZZ) -4 (methoxyimino) -2- (5-thioxo-4,5-dihydro-1) protected intermediate. 3,4-oxadiazol-2-yl) -1-pyrrolidinecarboxylate as a yellowish oil (200mg, 23%).

¹ H-NMR (CDCl ₃ ): 1.46 (m, 9H, CH 3), 2.7-3.3 (m, 2H, CH 2), 3.88 (s, 3H, CH 3 O), 4.05-4.35 (m, 2H, CH 2), 5.29 (m, 1 H, CH-N). MS (APCI) 313.0.

The N-protected intermediate from the above step, tert-butyl (2S, 4ZZ) -4 (methoxyimino) -2- (5-thioxo-4,5-dihydro-1,3,4-oxadiazole-2- yl) -1-pyrrolidinecarboxylate (0.64 mmol; 200mg) was dissolved in dry DCM (25ml) at 0 ° C and HCl gas was bubbled through the solution for 20min. The solvent was evaporated and the residue was redissolved in DMC and evaporated. The residue was redissolved in dry DCM (20ml) and triethylamine (5.12mmol; 518mg) was added, followed by slow addition of an N-capping agent such as [1,1'-biphenyl] -4-carbonyl chloride (0.64mmol; 139mg) which previously dissolved in DCM at 0 ° C; the reaction mixture was stirred at room temperature overnight. To the mixture was then added 200 mg of Pol-trisamine (3.45 mmol / g) to rinse the acyl chloride, and the reaction was stirred for an additional 5 hours, then filtered and the filtrate was rinsed with saturated NH ₄ Cl solution and brine, dried over Na ₂ SO ₄ and the solvent was evaporated. The crude product was purified by FC using a linear gradient of 40:60 (EtOAc: cyclohexane) to 90:10 (EtOAc: MeOH) over high speed 37 minutes to give the title compound, (3EZ, 5S) -1 - ([1,1 '] -biphenyl] -4-ylcarbonyl) -5- (5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) -3-pyrrolidinone O-methyloxime (40mg, 16%).

¹ H-NMR (CDCl ₃ ): 2.8-3.2 (m, 2H, CH 2), 3.9 (s, 3H, CH 3 -O), 4.2-4.5 (m, 2H, CH 2), 5.95 (m, 1H, CH- N, 7.3-7.7 (m, 9H, Ar). MS (APCI &lt; ⁺ &gt;):395.0; MS (APCI +): 393.0.

- 125 Example 80:

General method for the synthesis of the dissolved phase of pyrrolidine oxadiazole derivatives of the general formula I, where B = III, X = O (scheme 9,11):

5- (2S, 4EZ) -1- (1,1,1-biphenyne-4-carbonyl) -4- (methoxyimino) pyrrolidine-1,3,4oxadiazol-2 (3H) -one

To a stirred solution of tert-butyl (2S, 4EZ) -2- (hydrazinocarbonyl) -4 (methoxyimino) -1-pyrrolidinecarboxylate (intermediate 9, 1.84 mmol; 500 mg) and triethylamine (2.76 mmol; 279 mg) in THF ( 25mL) 1,1'-carbonyldiimidazole (2.76 mmol; 448 mg) was added at 0 ° C. Stirring was continued for 5 hours. Another portion of triethylamine and 1,1'-carbonyldiimidazole was added and stirring was continued at room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc and washed with saturated NH ₄ Cl solution and 10% NaHCO ₃ , and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated to dryness to give the N -protected intermediate, tert -butyl (2S, 4E) -4- (methoxyimino) 2- (5-oxo-4,5-dihydro-1, 5-oxo-4,5-dihydro-1,2,3,4-dihydro-1,2,3,4-dihydro) -1 3,4-oxadiazol-2-yl) -1-pyrrolidinecarboxylate as a white foam (460mg, 84%).

¹ H-NMR (CDCl ₃ ): 1.46 (s, 9H, CH 3), 2.8-3.25 (m, 2H, CH 2), 3.88 (s, 3H, CH 3 O), 4.05-4.35 (m, 2H, CH 2), 5.06 (m, 1 H, CH-N). MS (APCl +): 297.0.

Chrá-protected intermediate from the above step, tert-butyl (2S, 4E) -4 (methoxyimino) -2- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) -1 -pyrrolidine carboxylate, was subjected to the same conditions to remove N a protection

126 subsequent N-acylation as described in Example 49, whereby purification by flash chromatography affords the title compound, (5 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4ylcarbonyl) -4 - (methoxyimino) -pyrrolidinyl] -1,3,4-oxadiazol-2 (3H) -one (130mg, 26%).

1 H-NMR (CDCl 3): 2.8-3.1 (m, 2H, CH 2), 3.84 (s, 3H, CH 3 -O), 4.2-4.5 (m, 2H, CH 2), 5.75 (m, 1H, CH-N) 7.35-7.7 (m, 9H, Ar). MS (APCI &lt; ⁺ &gt;):379.0; MS (APCI) 377.0.

Example 81:

General method for synthesizing the dissolved phase of pyrrolidine oxadiazole derivatives of formula I wherein B is a substituent of formula IV, X = a bond, R ⁸ = H (Scheme 9,11);

(3EZ, 5S) -1- (η 1,1'-biphenyl-4-ylcarbonyl) -5- (1,3,4-oxadiazol-2-yl) -3-pyrrolidinone

O-methyloxime o

t

To a solution of tert-butyl (2S, 4EZ) -2- (hydrazinocarbonyl) -4- (methoxyimino) -1-pyrrolidinecarboxylate (intermediate 9, 2.86 mmol; 780 mg) in TMOF (8mL) was added 3 drops of acetic acid and the reaction mixture was heated 4 hours at 80 ° C, then overnight at room temperature. The solvent was evaporated to dryness to give a yellowish foam (610mg). The residue was redissolved in toluene and P ₂ O _{5 was added} . The reaction mixture was heated to reflux for 2.5 hours, then the solvent was removed. Water was added to the residue and the solution was extracted with EtOAc. The organic layer was washed with saturated NH ₄ Cl solution and brine to give the desired N-protected intermediate, target-127-.

butyl (2S, 4E) -4- (methoxyimino) -2- (1,3,4-oxadiazol-2-yl) -1-pyrrolidinecarboxylate as a yellow oil (330 mg, 63%). ¹ H-NMR analysis revealed that the product was present in a purity of> 90%. The compound was considered pure enough to be used in subsequent steps without further purification (only 2 sites on TLC, Pancaldi determination corresponding to E- and Z-isomers, R _f = 0.35 and 0.47, eluting with EtOAc: hexane 1: 1).

¹ H-NMR (CDCl 3): 1.46 (broad m, 9H, CH 3), 2.8-3.3 (m, 2H, CH 2), 3.89 (s, 3H, CH 3 -O), 4.05-4.3 (m, 2H, CH 2) 5.4 (m, 1 H, CH-N). MS (APCI ^&lt; ^{+ &gt;} ): 283.0.

The N -protected intermediate from the above step, tert-butyl (2S, 4E) -4 (methoxyimino) -2- (1,3,4-oxadiazol-2-yl) -1-pyrrolidinecarboxylate, was subjected to the same removal conditions. N-protection followed by N-acylation as described in Example 49 to give the title compound, (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5 after purification by flash chromatography. - (1,3,4-Oxadiazol-2-yl) -3-pyrrolidinone O-methyloxime (80mg, 10%).

¹ H-NMR (CDCl 3): 2.8-3.2 (m, 2H, CH 2), 3.65 (s, 3H, CH 3 -O), 4.2-4.45 (m, 2H, CH 2), 5.95 (m, 1H, CH-N) 7.3-7.6 (m, 9H, Ar), 8.2 (s, 1H, CH hetero). MS (APCI ^&lt; ^{+ &gt;} ): 363.4.

Example 82:

General method for the synthesis of the dissolved phase of pyrrolidine oxadiazole derivatives of the formula I, wherein B is a substituent of formula IIb, R ⁷ = H:

(3EZ, 5S) -1 - ([1,1'-Biphenyl-4-ylcarbonyl) -5- (1,2,4-oxadiazol-3-yl) -3-pyrrolidinone

O-methyloxime

- 128 -

To a suspension of (2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -N'-hydroxy-4- (methoxyimino) -2-pyrrolidinecarboximidamide (interm. 8, 170mg, 0.48mmol) in TMOF (20ml) was added a catalytic amount of p-toluenesulfonic acid and the reaction mixture was heated to reflux for 16 hours. The TMOF was then evaporated in vacuo and the residue was dissolved in DCM (15 mL). The solution was washed with aqueous NaHCO ₃ (aq) (2 x 15 mL), dried over MgSO ₄ and evaporated in vacuo. Silica gel chromatography, eluting with 15% EtOAc in hexanes gave the desired product, (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (1,2,4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime (59mg).

¹ H-NMR (400MHz, CDCl ₃ ): 2.9 (m, 1H), 3.2 (m, 1H), 3.9 (m, 3H), 4.3-4.6 (m, 2H), 6.1 (m, 1H), 7.3- 7.7 (m, 9H, 8.7 (s, 1 H)) MS (APCI ⁺ ): 363.2.

Example 83:

Production of pharmaceutical formulation

Formulation 1 - Tablets

The pyrrolidine oxadiazole compound of formula (I) is admixed as a dry powder with dry gelatin binder in an approximate 1: 2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is processed in a tablet press to 240-270 mg tablets (80-90 mg active pyrrolidine oxadiazole compound per tablet).

Formulation 2 - Capsules

The pyrrolidine oxadiazole compound of formula (I) is admixed as a dry powder with a starch diluent in an approximate 1: 1 weight ratio. »» · · ·

- 129 are filled into 250 mg capsules (125 mg active pyrrolidine oxadiazole compound per capsule).

Formulation 3 - Liquid

The pyrrolidine oxadiazole compound of formula (I), sucrose and xanthan gum are mixed, passed through a 10 mesh U.S. sieve. and then mixed with a pre-prepared solution of microcrystalline cellulose and carboxymethylcellulose sodium (11:89) in water. Sodium benzoate, flavor, and color are dissolved in water and added with stirring. Sufficient water is then added.

Formulation 4 - Tablets

The pyrrolidine oxadiazole compound of formula (I) is admixed as a dry powder with dry gelatin binder in an approximate 1: 2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is processed on a tablet press to 450-900 mg tablets (150-300 mg active pyrrolidine oxadiazole compound).

Formulation 5 - Injection

The pyrrolidine oxadiazole compound of formula (I) is dissolved in a buffered sterile saline injectable aqueous medium to produce a convenient concentration.

Example 84: Biological tests

Compounds of formula (I) may be subjected to the following tests:

a) In vitro competition binding assay using Scintillating Proximity Assay (Pharmaceutical Manufacturing International, 1992, pp. 49-53, Cook, N.D. et al)

This assay makes it possible to determine the affinity of test compounds for the OT receptor. Membranes from HEK293EBNA cells expressing the hOT receptor were resuspended in a buffer containing 50 mM Tris-HCl, pH 7.4, 5 mM MgCl ₂ and 0.1% BSA (w / v). Membranes (2-4 µg) were mixed with 0.1 mg wheat-130 gm agglutinin (WGA) SPA bead (type A) and 0.2 nM radiolabeled [125 |] _ovTA (OVTA is Ornithin Vasoactiv and is an analogue of OT for competitive binding experiments) . Non-specific binding was determined in the presence of 1 μΜ oxytocin. The total assay volume was 100 µl. Plates (Corning ® NBS plate) were incubated at room temperature for 30 minutes and counted on a Mibrobeta counter. Test compounds were used at concentrations of 30 pM, 10 pM, 1 pM, 300 nM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM. Competence binding data was analyzed using an iterative, non-linear, suitable curve fitting program, Prism.

The receptor binding affinities of the oxytocin pyrrolidine derivatives of formula (I) were determined using the above in vitro bioassay. Representative values of some examples of compounds are shown in Table 1 below. The values represent the binding affinity (IC ₅₀ ; pM) of an example of compounds of formula (I) to the oxytocin receptor.

- 131 «. · «· · ·

Table 1:

Structural formula Name-IIIPAC Human OT-R Binding Affinity (ICsofpM) —0, OH ° ” ^N (3 EZ, 5S) -1 - ([1,1'-biphenyl-4-ylcarbonyl) -5 {3 - [(1RS) -1-hydroxypropyl] -1,2,4-oxadiazol-5-yl} -3-pyrrolidinorl · 0-methyloxime * 0.006 'XqyX < _N b - ^N 0> = 0 (3 EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5 {3- [2-oxo-2- (1-pyrrolidinyl) ethyl] -1,2,4-oxadiazole -5-yl} -3-pyrrolidinone methyl-oxime 0.007 O ýM XA OH (3'Z, 5S) -1 - ([1,1'-biphenyl-4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinoride-O- methyloxim 0.011 O N νΑ , -γΌΧ O 0 (3 EZ, 5S) -5- (5- (1-acetyl-4-piperidinyl) -1,2,4-oxadiazol-3-yl) -1 - ([1,1'-biphenyl] -4ylcarbonyl) -3 -pyrrolidinone O-methyioxime 0.002 "O _N TV7 ΓΎ P ^ ⁰ ^ ^N ~ Q ⁰ N - ({3 - [(2S, 4ZZ) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazol-5-yl (methyl) acetamide 0.003

-132Table 1 - continued:

Structural formula IUPAC-Name Human OT-R binding affinity IC ₅₀ (μΜ) ' ^x o Ň 0 0. N (3S, 5S) -1 - ([1,1'-Biphenyl-4-ylcarbonyl) -5 (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone-O-methyloxime 0.088 ^x o N 0 0. N (3'Z, 5S) -1 - [(2'-Methyl [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime 0.021 ^x o N O-nA, ⁰ O ^ N (3'Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5 (1,3,4-oxadiazol-2-yl) -3-pyrrolidinone O-methyl-oxime 0.211 I T ° ΓΗλΑ-ι \ = / O ° - _N ^ (3 E, 5S) -1 - [(2'-Methyl [1,1'-biphenyl-4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3- pyrrolidinone O-methyloxime 0.023 1 % O (3Z, 5S) -1 - [(2'-Methyl [1,1'-biphenyl] -4yl) carbonyl] -5- (3-methyl-1,2,4-ox adiazol-5-yl) -3-pyrrolidinone <. O-methyloxime 0.009

According to a preferred embodiment, the compounds have a binding affinity (/ C ₅ o (μΜ)) of less than 0.40 μΜ, more preferably less than 0.1 μΜ.

- 133 -

b) Functional test 1: Inhibition of Ca ² * -mobilization by FLIPR (Fluorescent Imaging Plate Reader)

FLIPR is a fluorescence imaging device using a laser that is capable of illuminating a 96-well plate and represents simultaneous reading of each well and therefore allows rapid measurement of a large number of samples.

This test shows the inhibition of calcium mobilization by OT / OT-R necessary for uterine contractions - using the test compounds of formula (I).

Plate preparation: FLIPR plates were pre-coated with PLL (Poly-L-Lysine) 10µg / ml + 0.1% gelatin to collect HEK (Human Embryonic Kidney) cells at 37 ° C for 30 minutes to 2 days. Cells were transferred to 96-well plates (60,000 cells / well).

Fluo-4 labeling: 50 µg of fluo-4 (fluorescent marker) was dissolved in 20μΙ pluronic acid (20% in DMSO). Dissolved fluo-4 was then diluted in 10ml of DMEM (Dubecco's Minimal Essential Medium-F12 medium without FCS (Fetal Calf Serum). The medium was removed from the plates followed by a single flush with DMEM-F12. fluo-4, and the cells were incubated for 1-1.5 hours (CHO cells) and 1.5-2 hours (HEK cells) The cells now contain a fluorescent marker.

Buffer: 145 mM NaCl, 5 mM KCl, 1 mM MgCl ₂ , 10 mM Hepes, 10 mM glucose, EGTA (ethylene-bis-oxyethylene nitrilo tetraacetic acid). Adjusted to pH 7.4.

Test Performance: A minimum of δθμΐ / well antagonist (5x) in the above buffer (1x) was prepared (96-well plates). Antagonists were added to the well plates at various concentrations (30 pM, 10 pM, 1 pM, 300 nM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM).

OT is added at a concentration of 40 nM.

A fluorescent marker that is sensitive to the amount of Ca ²⁺ mobilized within the cell can be quantified by a FLIPR.

The activities of the pyrrolidine derivatives of formula (I) were determined using the in vitro bioassay described above. Representative values for some examples of compounds are shown in Table 2 below. The values represent the capacity of the examples of compounds of formula (I) to effectively antagonize oxytocin-induced intracellular Ca ²⁺ mobilization by the oxytocin receptor.

- 135 · · V 135 135 · 135 135 135 135 135 135 135 V 135 135 135 135 135 135 V 135 135 V V V V V V V V V V V V V · · · · · · · · · · · · · · ·

Table 2:

, Structural Formula IUPAC-Name inhibition of Ca ² '-, mobilization, hOT-R IRso (μΜ) ^x o I N o 0. <KN (3EZ, 5S) -1 - ((1,1'-Biphenyl) -4-yicarbonyl) -5 (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone · 0-methylicime 0.004 ^ 0 and N o o. N (3EZ, 5S) -1 - [(2'-Methyl [1,1'-biphenyl] -4yl) carbonyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone 0 -methyloxim 0.012 ^x o I N oo -U ⁰ ° ^ ^N (3 EZ, 5 S) -1 - ([1,1'-y I J-4-ylcarbonyl I> -5 (1.3 _t 4-oxadiazol-2-yl) -3-pyirolidinon 0methyloxim 0.220 0 - and N σ _ο ύ 0 N? ^ == N (3EZ, 5S) -1 - [(2'-Chloro [1,1'-biphenyl] -4yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methylnyxime 0.001 AND % \ == / 0 (3Z, 5S) -1 - {(2'-Methyl [1,1'-biphenyl] -4yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinori O-methyl oxime 0.004

- 136 (c) Functional test 2: Inhibition of IP3 synthesis (Inositol Tri-Phosphat) in HEK / EBNA-OTR cells

This assay shows the inhibition of IP3 synthesis by OT / OT-R, which is necessary for uterine contractions, using the test compounds of formula (I).

Cell Stimulation: HEK / EBNA OTR cells (rat or human) were placed in 12-well plates (costar) and equilibrated for 15-24 hours with a radiolabeled [ ³ H] -1 carrier in a medium without addition of inositol 1% FCS (0.5ml / well). 4 pCi / ml was used. Then the labeled environment was aspirated. Then DMEM (without FCS, inositol), 20mM Hepes (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid), 1mg / ml BSA containing 10mM LiCl were added over 10-15 minutes at 37 ° C. (freshly prepared). An agonist (e.g., oxytocin used at a concentration of 10 nM) and antagonists (e.g., test compounds of formula (I) used at a concentration of 10 pM, 1 pM, 300 nM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM, 3 pM) were added during the desired time (15-45 min) and then the environment was aspirated. By antagonizing the OT receptor, radiolabeled inositol was phosphorylated to give IP3, the amount of radiolabeled IP3 can be determined during subsequent processing. The reaction was quenched with 1 ml STOP solution (e.g. 0.4 M perchloric acid) and allowed to stand for 5-10 minutes at room temperature. Then, 0.8 mL was transferred to tubes containing 0.4 mL of neutralization solution (0.72 Μ KOH / 0.6M KHCO ₃ ), and the tubes were swirled and left to cool for at least 2 hours.

IP Separation: Samples were centrifuged at 3000-4000 rpm for 15 minutes. The supernatant (1 mL) was transferred to new tubes containing 2.5 mL of H ₂ O. The solid resin (0.8 mL) was equilibrated with 20 mL of H ₂ O and the whole samples were poured from the chromatography column to separate the mixture. Two washes of 10 ml of water were performed to remove free inositol.

Total IP elution: Elution was achieved using a mixture of 3 ml of 1M ammonium formate / 0.1 M formic acid. The eluent was collected in scintillation counters

- 137 · trub trub trub 137 137 137 137 137 a a a a a a a a a a a a a a a a a a a a a a a a a a a a a 7 ml of scintillation fluid was then added. The amount of IP3 is determined by a scintillation counter.

d) In vivo model of uterine contraction inhibition

The test shows the biological effect of test compounds in a model of premature labor and premature labor in vivo.

Non-pregnant female Charles River CD (SD) BR rats (9-10 weeks old, 200250g) were treated 18 and 24 hours prior to the experiment with 250 pg / kg, i.p. diethylstilbestrol (DES). For the purpose of the test, the animals were anaesthetized with urethane (1.75 g / kg, i.p.) and placed on a placed homeothermic operating table. The trachea was isolated and cannulated with a suitable polyethylene (PE) tube. A middle incision was made at the hypogastric level and one uterine outgrowth was exposed, its cephalic end was cannulated with a PE240 tube and after filling the inner cavity 0.2 ml of sterile physiological saline was connected to the “Gemini” magnification / recording system using a P23ID Gould Statham of said pressure. For i.v. of the test compounds, one jugular (jugular vein) was isolated and cannulated with a PE60 tube connected to a wing needle for administration by a dispenser syringe. For intraduodenal administration of test compounds, the duodenum (duodenum) was isolated and similarly cannulated with a small incision in its wall. One carotid artery was also isolated and cannulated with a PE60 catheter and attached to a suitable syringe for blood samples (see below). After stabilization, the same dose of oxytocin was repeatedly injected intravenously at 30 minute intervals. When comparable contractile uterine responses to the selected dose of oxytocin were obtained, the test compound was administered at concentrations of 0.3; 1; 3; 10 mg / kg (5 ml / kg infusion; iv) and 30 mg / kg (7.5 ml / kg infusion; iv), as well as concentrations of 3 and 10 mg / kg (5 ml / kg; per os), 30 mg / kg (7.5 ml / kg; per os) as well as 60 mg / kg (10 ml / kg; per os). Subsequent injections of the same dose of oxytocin were then performed at an appropriate time after treatment to determine the inhibitory effects of the test compounds. The uterine contractile responses to oxytocin were quantified by measuring intrauterine pressure and the number of contractions.

- 138 • ························ «• X ·· · · · ·

A total of six animals form one group that is treated with the test compound at the indicated concentrations (see above).

The effect of the test compounds was evaluated by comparing the pressure values before and after treatment. In addition, 2, 30, 90 and 210 minutes after administration of the test compound, 0.5 ml blood samples were taken from the cannulated cervix of each test animal. Plasma was obtained by standard laboratory method and the resulting samples were stored at -20 ° C.

The effects of the pyrrolidine derivatives of formula (I) were determined using the in vivo bioassay described above. Representative values of one example compound are shown in Table 3 below. The values represent the capacity of an example of a compound of formula (I) to effectively antagonize oxytocin-induced uterine contractions in the rat.

- 139 ····· · · Λ · · · ·

Table 3

Represented by:

- 140 · * 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 · ♦ · ·

Pt · 'Wi-wí

Claims (25)

Patent claims Pyrrolidine oxadiazole derivatives according to formula (I) and also their geometric isomers, their optically active forms such as enantiomers, diasteromers, and their racemate forms, as well as their pharmaceutically acceptable salts, wherein: A is selected from the group consisting of - (C = O) -, - (C = O) -O-, -SO ₂ -, -SO ₂ NH-, -CH ₂ -; B an oxadiazole or thiadiazole ring; R ^{1 is} selected from the group consisting of or consisting of C 1 -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, heteroaryl, C 1 -C ₆ alkyl aryl, C 1 -C 6 alkyl heteroaryl, R ¹ may form with the O atom to which it is attached a 3- to 8-membered, saturated or unsaturated heterocyclic ring, which may contain 1-2 additional heteroatoms selected from N, S and O, and which is optionally linked to aryl, heteroaryl or 3- to 8-membered saturated or unsaturated cycloalkyl ring; R ^{2 is} selected from the group consisting of or consisting of C 1 -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, heteroaryl, heteroarylalkyl, 3-8 membered cycloalkyl, acyl, C 1 -C 6 _s -alkyl aryl, C 1 -C 8 -alkyl heteroaryl, wherein said cycloalkyl or aryl groups or 141 heteroaryl may be linked to 1-2 other cycloalkyl or aryl or heteroaryl groups; R ^3, R ^4, R ⁵ and ^R are independently selected from the group consisting of H, halogen, _Ci-C6 alkyl or _Ci-C5 alkoxy. Second Pyrrolidine oxadiazole derivative according to claim 1 wherein R ¹ is selected from the group consisting of H or -C, -C _s -alkyl, especially -CH _third The pyrrolidine oxadiazole derivative according to claim 1 or 2, wherein A is - (C = O) -. A pyrrolidine oxadiazole derivative according to any one of the preceding claims, R ² is an aryl or heteroaryl group. The pyrrolidine oxadiazole derivative according to claim 4, wherein R ^{2 is} a phenyl group. The pyrrolidine oxadiazole derivative according to claim 5, wherein said phenyl group is substituted with a phenyl group. A pyrrolidine oxadiazole derivative according to any one of the preceding claims, wherein B is an oxadiazole of formula (IIa) or (IIb) N> - °> (IIb) 'Ar wherein R ⁷ is selected from the group comprising or consisting of H, sulfonyl, amino, Ci-C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C _s -alkynyl wherein said alkyl, alkenyl, alkynyl chains may be interrupted by a heteroatom selected from N, O or S, aryl, heteroaryl, saturated or unsaturated 3- to 8-membered cycloalkyl, heterocycloalkyl groups, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be connected with - 142 - 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, the acyl radical, C ₆ -alkyl aryl, C ₆ -alkyl heteroaryl, C ₆ -alkenyl aryl, C -C alkenyl-heteroaryl, O-CE- alkynyl aryl, C ₆ -alkynyl heteroaryl, C, -C ₆ -alkyl cycloalkyl, C _e -alkyl heterocycloalkyl, C ₆ -alkenyl cycloalkyl, C ₆ -alkenyl heterocycloalkyl, C ₆ -alkynyl cycloalkyl, C 1 -C ₆ -alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, C 1 -C ₆ -alkyl carboxy, C 1 -C ₆ -alkyl acyl, aryl acyl, heteroaryl acyl, C ₃ -C ₈ - (hetero) cycloalkyl acyl, C 1 -C ₆ -alkyl acyloxy, C 1 -C ₆ -alkyl alkoxy, C 1 -C ₅ -alkyl alkoxycarbonyl, C 1 -C ₆ -alkyl aminocarbonyl, C 1 -C ₆ -alkyl acylamino, acylamino, C 1 -C ₆ -alkyl ureido, C 1 -C ₆ - alkyl carbamates, Ci-Ce-alkyl, amino, _Ci-C -alkyl ammonium, C ₆ -alkyl sulfonyloxy, _Ci-C6-alkyl sulfonyl, (ΧCe alkyl sulfinyl, _Ci-C6-alkyl sulfanyl, C C _e -alkyl sulfonylamino, C _alkyl aminosulfonyl, hydroxy or halogen. 8th Pyrrolidine oxadiazole derivative according to claim 7, wherein R ⁷ is selected from the group consisting of a sulfonyl or an amino residue or a C -C _alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, heteroaryl, A 3- to 8-membered cycloalkyl group optionally containing at least one heteroatom selected from N, O, S, C 1 -C ₆ -alkyl aryl, C 1 -C ₆ -alkyl heteroaryl, C 1 -C 6 -alkenyl aryl, C 1 -C ₆ -alkyl C ₆ -C ₆ -alkenyl heteroaryl, alkoxycarbonyl, carboxylamide, C 1 -C 6 -alkyl carbonyl, arylcarbonyl or heteroarylcarbonyl, C ₄ -C ₆ -cycloalkylcarbonyl, wherein the above groups are substituted by at least one sulfonyl or amino radical. The pyrrolidine oxadiazole derivative according to claim 8, wherein R ^{7 is} selected from the group consisting of C 1 -C ₆ -alkyl amino, heterocycloalkyl, C 1 -C ₆ -alkyl heterocycloalkyl, aminocarbonyl, C 1 -C 6 alkylamino carbonyl, C 1 -C ₆ alkyl acyl amino, C 1 -C ₆ -alkyl sulfonyl or C 1 -C ₆ -alkyl. The pyrrolidine oxadiazole derivative according to claim 9, wherein R ⁷ is selected from the group consisting of dimethyl aminomethyl, 2- (dimethylamino) ethyl, -methyl-3-piperidinyl or 4- (acetyl-1-piperazinyl) methyl. - 143 · · 143 143 143 143 143 143 143 143 143 143 9 9 9 9 9 9 9 9 9 9 9 9 9 9 A pyrrolidine oxadiazole derivative according to any one of claims 1 to 10, wherein B is an isoxadiazole of formula (III) or (IV) wherein X is O or S; R ₈ is hydrogen, C 1 -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, heteroaryl, saturated or unsaturated 3- to 8-membered cycloalkyl, optionally containing 1 to 3 heteroatoms , selected from N, O, S, acyl radical, C 1 -C ₆ -alkyl aryl, C 1 -C ₆ -alkyl heteroaryl, C 1 -C ₆ -alkenyl aryl, C 1 -C ₆ -alkenyl heteroaryl, alkoxycarbonyl, carboxylamide, C 1 -C ₆ - alkoxy, aryloxy, heteroaryloxy, halogen, cyano, C ₁ -C ₆ -alkyl carbonyl, arylcarbonyl or heteroarylcarbonyl, saturated or unsaturated C ₄ -C ₈ -cycloalkylcarbonyl, wherein said cycloalkyl or aryl or heteroaryl groups may be linked to 1-2 other cycloalkyl groups or ary ! or heteroaryl and wherein said alkyl, alkenyl, alkynyl chain may be interrupted by a heteroatom selected from N, O or S. A pyrrolidine oxadiazole derivative according to any one of the preceding claims, wherein each of R ³ , R ⁴ , R ⁵ and R ⁶ is H. A pyrrolidine oxadiazole derivative according to any one of the preceding claims, wherein A is - (C = O) -, R ¹ is a methyl group, R ² is a biphenyl group, each of R ³ , R ⁴ , R ⁵ and R ⁶ is H and B the oxadiazole ring of formulas (IIIa), (IIb), (IIIa) or (IV). - 144 The pyrrolidine oxadiazole derivative according to claim 13, wherein the B oxadiazole ring of formulas (IIa) or (IIb). A pyrrolidine oxadiazole derivative according to any one of the preceding claims, selected from the following group: (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ) 1,5S) -1 - [(2'-methyl [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O -methyl-oxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (1,3,4-oxadiazol-2-yl) -3-pyrrolidinone O-methyl-oxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-thioxo-4,5-dihydro-1,3,4oxadiazol-2-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- (3-benzyl-1,2,4-oxadiazol-5-yl) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1- ( [1,1'-biphenyl] -4-ylcarbonyl) -5- (3 - {[(2-furylmethyl) sulfanyl] methyl} -1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3- [2-oxo-2- (1-pyrrolidinyl) ethyl] -1,2,4-oxadiazol-5-yl -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(2-pyridinylsulfanyl) methyl] -1,2,4-oxadiazole-5} -yl} -3-pyrrolidine on O-methyloxime (3EZ, 5S) -1 - ([1,1´-biphenyl] -4-ylcarbonyl) -5- [3- (4-fluorophenyl) -1,2,4-oxadiazole 5-yl] -3-pyrrolidinone O-methyloxime - 145 (3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- {3 - [(2-thienylsulfanyl) methyl] 1,2,4-oxadiazol-5-yl} - 3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3- [2- (3,5-dimethyl-1H-pyrazol-1-yl)] (ethyl) -1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(methylsulfonyl) methyl] -1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (5-methyl-3-isoxazolyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4- ylcarbonyl) -5- [3- (2-thienylmethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1, T-biphenyl] - 4-ylcarbonyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (3 - {[(2-furylmethyl) sulfonyl] methyl} -1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- [3- (aminomethyl) -1,2,4-Oxadiazol-5-yl] -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1] 1-Biphenyl] -4-yl Rbonyl) -5- {3 - [(R, S) -hydroxy (phenyl) methyl] 1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([ 1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(1ES) -1-hydroxypropyl] -1,2,4-oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (hydroxymethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(1S, 2R) -2-hydroxycyclohexyl] 1,2,4-oxadiazol-5-yl} -3- pyrrolidinone O-methyloxime - 146 - (3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] - 3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (4-piperidinyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(3RS) -piperidinyl] -1,2,4-oxadiazole 5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {3 - [(2RS) -piperidinyl] -1,2 4-Oxadiazol-5-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - [(2'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl) -1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -1 - {[ 2 '- (trifluoromethyl) [1,1-biphenyl] -4-yl] carbonyl} -3-pyrrolidinone O-methyloxime (3Z, 5S) -1 - [(2'-fluoro [1,1'-biphenyl] -4] -yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - [(4'-fluoro [1, T] -biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'- biphenyl] -4-ylcarbonyl) -5- (1,2,4-oxadiazol-3-yl) -3-pyrrole olidinone O-methyloxime (3E, 5S) -1 - [(2'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-Pyrrolidinone O-methyloxime (3E, 5S) -1 - [(2'-methyl [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazole) -5-yl) -3-pyrrolidinone O-methyloxime (3Z, 5S) -1 - [(2'-methyl [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1) (2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime - 147 · · 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 - 3 - - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (phenoxymethyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1- ( [1,1'-Biphenyl] -4-ylcarbonyl) -5- (5-phenyl-1,2,4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime N - ({3 - [(2S, 4 (Z) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} methyl) acetamide (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5- [4- (hydroxymethyl) phenyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (2-hydroxyethyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-Biphenyl] -4-ylarbonyl) -5- {5 - [(2S) -2-hydroxy-2-phenylethyl] 1,2,4-oxadiazol-3-yl -3-pyrrolidinone O-methyloxime {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazole-5- yl} methylformamide (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (methoxymethyl) -1,2,4-oxadiazole ol-3-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (2-phenoxyethyl) -1,2 4-Oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (2-methoxyethyl) -1, 2,4-Oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- [5- (1-acetyl-4-piperidinyl) -1,2,4-oxadiazol-3-yl] -1 - ([1,1'-Biphenyl] 4-ylcarbonyl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (2 -pyridinyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime 148- (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (3-thienyl) -1,2,4-oxadiazol-3-yl] -3 -pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-ethyl-1,2,4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-cyclopentyl-1,2,4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-methyl-1,2,4-oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(RS) -hydroxy (phenyl) methyl] 1,2,4-oxadiazol-3-yl} -3 -pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(1RS) -1-hydroxy-2-phenylethyl] -1,2,4 -oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(1R) -1- (dimethylamino) (2-Phenylethyl) -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [ 5- (3-pyridinyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (4-pyridinyl) -1,2,4-oxadiazole- 3-yl] -3-pyrrolidinone O-methyloxime (3Z, 5S) -5- {5 - [(4-acetyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-3-yl} -1 - ([ 1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- [3- (1-acetyl-4-piperidinyl) -1,2,4-oxadiazol-5-yl] ] -1 - ([1,1'-biphenyl] 4-ylcarbonyl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- {5 - [(4-acetyl-1-piperazinyl) methyl] -1, 2,4-Oxadiazol-3-yl} -1 ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime - N - ({3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} methyl) -3- (1-piperidinyl) propanamide (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- { 5 - [(3S) -1-methylpiperidinyl] 1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3R, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) ) -5- {5 - [(3R) -1-methylpiperidinyl] 1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3'Z, 5S) -1 - ([1,1 ' -biphenyl] -4-ylcarbonyl) -5- [5- (6-hydroxy-3-pyridinyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3Z, 5S) -1- ( [1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(dimethylamino) methyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3'Z, 5S) -5- {5 - [(1S, 2R) -1-amino-2-hydroxypropyl] -1,2,4-oxadiazol-3-yl} -1 ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(3S) -piperidinyl] -1,2,4-oxadiazole- 3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(3E) -piperidinyl] -1,2 , 4-Oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5ES) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [5- (1-methyl-3-piperidinyl) 1,2,4-oxadiazole -3-yl] -3-pyrrolidinone O-methyloxime tert-butyl (3ft) -3- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) -pyrrolidinyl] -1,2,4-oxadiazol-5-yl} -1-piperidinecarboxylate 4 - ({3 - [(2S, 4ZZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl (methyl) -2,6-piperazinedione (3Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazole-5] -yl] -3-pyrrolidinone O-methyloxime - 150 • (3Z, 5S) -1 - [(2'-chloro-4'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) - 5- [5- (1-Methyl-4-piperidinyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl] - 4-ylcarbonyl) -5- {5 - [(dimethylamino) methyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1,1'-biphenyl) 4-ylcarbonyl) -5- [3- (1-methyl-4-piperidinyl) -1,2,4oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- {5 - [(1S) -1-amino-2-hydroxyethyl] -1,2,4-oxadiazol-3-yl} -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime 5 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] - N - [3- (dimethylamino) propyl] -1,2,4 oxadiazole-3-carboxamide (3E, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(dimethylamino) methyl] -1,2,4oxadiazol-3-yl 3-pyrrolidinone O-methyloxime tert-butyl (3S) -3- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) - pyrrolidinyl] -1,2,4-oxadiazol-5-yl} -1-piperidinecarboxylate (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(4 -methyl-1-piperazinyl) methyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime (3Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- {5 - [(4-methyl-1-piperazinyl) methyl] 1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime ethyl 5 - [(2S, 4EZ) -1- ( [1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazole-3-carboxylate (3E, 5S) -1 - ([1,1'-biphenyl) 4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime 151- (3Z, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime N - ({3 - [(2S, 4EZ) -1 - ([1,1'-bitenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4 -oxadiazol-5-yl} methyl) -3- (dimethylamino) propanamide tert-butyl 4- (2- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl-4-methoxyimino) pyrrolidinyl] - 1,2,4-Oxadiazol-5-yl} ethyl) -1-piperazinecarboxylate (3EZ, 5S) -1 - [(2'-chloro-4'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- [3- (2-hydroxyethyl) -1,2,4-oxadiazol-5-yl] -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - [(4'-fluoro-2'-methyl) [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -1 - ([1, 1'-Biphenyl] -4-ylcarbonyl) -5- {5- [2- (dimethylamino) ethyl] -1,2,4-oxadiazol-3-yl} -3-pyrrolidinone O-methyloxime 2- {5 - [(2S, 4ZZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazol-3-yl} ethyl [ (tert-butoxycarbonyl) amino] acetate N - ({3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl (methyl) -2- (dimethylamino) acetamide (3EZ, 5S) -1 - [(2'-chloro-4'-fluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3- methyl-1,2,4-oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime (3EZ, 5S) -5- {5 - [(1S) -1-amino-2-tert-butoxyethyl] -1,2,4 -oxadiazol-3-yl} -1 ([1,1'-biphenyl] -4-ylcarbonyl) -3-pyrrolidinone O-methyloxime tert-butyl 4- {5 - [(2S, 4EZ) -1 - ([1 1'-biphenyl] -4-ycarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-3-yl} -1-piperidinecarboxylate (3EZ, 5S) -1 - ([1,1 ' -biphenyl] -4-ylcarbonyl) -5- [5- (1-piperazinylmethyl) -1,2,4-oxadiazol-3-yl] -3-pyrrolidinone O-methyloxime 152-tert-butyl (4S) -4- {3 - [(2S, 4ZZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxy imino) pyrrolidinyl] - 1,2,4-Oxadiazol-5-yl} -4 - [(tert-butoxycarbonyl) amino] butanoate 4 - {[(2S, 4ZZ) -2- (5 - {[(tert-butoxycarbonyl) amino] methyl} -1,2,4-oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl] carbonyl} - 1,1'-biphenyl tert-butyl 2- {3 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2 4-oxadiazol-5-yl} ethylcarbamate 2- {5 - [(2S, 4EZ) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] 1,2,4-oxadiazol-3-yl} ethyl aminoacetate (3E) 1,5S) -1 - [(2 ', 4'-difluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4oxadiazol-5-yl) -3- pyrrolidinone O-methyloxime (3EZ, 5S) -1 - [(2 ', 4'-difluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4oxadiazole- 5-yl) -3-pyrrolidinone O-methyloxime 4 - {[(2S, 4EZ) -2- (5 - {(1S) -2-tert-butoxy-1 - [(tert-butoxycarbonyl) amino] ethyl} 1,2,4-oxadiazol-3-yl) -4 - (methoxyimino) pyrrolidinyl] carbonyl} -1,1'-biphenyl (3EZ, 5S) -1 - ([1,1'-biphenyl] -4-ylcarbonyl) -5- (5-vinyl-1,2,4) -oxadiazol-3-yl) -3-pyrrolidinone O-methyloxime 4 - {[(2S, 4ZZ) -2- (5 - {(1S, 2R) -2-tert-butoxy-1 - [(tert-butoxycarbonyl) amino] propyl} -1,2,4- oxadiazol-3-yl) -4- (methoxyimino) pyrrolidinyl] carbonyl} -1, t-biphenyl (3Z, 5S) -1 - [(2 ', 4'-difluoro [1,1'-biphenyl] -4-yl) carbonyl] -5- (3-methyl-1,2,4oxadiazol-5-yl) -3-pyrrolidinone O-methyloxime tert-butyl 4 - ({3 - [(2S, 4EZ) -1 - ([1,1] 1-Biphenyl] -4-ylcarbonyl) -4- (methoxyimino) pyrrolidinyl] -1,2,4-oxadiazol-5-yl} methyl) -1-piperazinecarboxylate - 153 - A pyrrolidine oxadiazole derivative according to any one of claims 1 to 15 for use as a medicament. Use of a pyrrolidine oxadiazole derivative according to any one of claims 1 to 15 for the manufacture of a pharmaceutical composition for the treatment and / or prevention of premature labor, premature labor and painful menstruation. Use of a pyrrolidine oxadiazole derivative according to any one of claims 1 to 15 for the manufacture of a pharmaceutical composition for modulating the oxytocin receptor. The use of claim 18, wherein said modulation consists in blocking the oxytocin receptor or antagonizing the binding of oxytocin to its receptor. Use according to claim 19 for the treatment or prevention of oxytocin receptor-mediated disorders. Use of a pyrrolidine oxadiazole derivative according to any one of claims 1 to 15 for the manufacture of a pharmaceutical composition for oral administration. A pharmaceutical composition comprising at least one pyrrolidine oxadiazole derivative according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier, diluent or excipient. A process for producing a pyrrolidine oxadiazole compound of formula (I) wherein B is A 1,2,4-oxadiazole group of formula (IIb), characterized in that a comprises the following step: XV VIII [B = lib] - 154 A process for producing a pyrrolidine oxadiazole compound of formula (I), wherein B A 1,2,4-oxadiazole group of formula (IIa), characterized in that it comprises the following step: in VI I [B = IIIa] A process for the preparation of a pyrrolidine oxadiazole compound of formula (I) wherein B is A 1,3,4-oxadiazole group of formula (III) or (IV), characterized in that it comprises both of the following steps: CDi (X = O) or CS ₂ (X = S) I [B = Hla (X = S)] I [B = Hlb (X = S)] Zastupuje;